Bis-1,3-diazine heterocyclic derivatives as antiarrhythmic agents

ABSTRACT

3-7-Diheterabicylo[3.3.1]nonanes and derivatives thereof are disclosed. Their method of preparation and use as antiarrhythmic agents is given.

This is a divisional of copending application Ser. No. 07/448,658 filedon 12/11/89, now U.S. Pat. No. 4,980,468.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to antiarrhythmic compositions. Morespecifically, the invention relates to certain3-7-diheterabicyclo[3.3.1]nonanes and derivatives thereof.

2. Description of the Prior Art

3-azabicyclo[3.3.1]nonanes, including bicyclic systems with oneheteroatom such as N, S and O and various derivatives, are known and aredocumented in the chemical literature. In a Chemical Reviews article,1981, Vol. 81, No. 2, pages 149-174, entitled "Chemistry of3-Azabicyclo[3.3.1.]nonanes" by R. Jeyaraman and S. Avila the synthesis,stereochemistry, and reactions of such compounds are reviewed. Thisarticle acknowledges the close resemblance of aza- and diazaadamantanesin conformation and stereochemistry to the 3-azabicyclo[3.3.1.]nonanesas a cause for significant progress in the azabicyclonane (ABN) studies.The article further acknowledges the ease of formation of 3-ABNs fromsimple ketones and aldehydes through the Mannich reaction without theinvolvement of complicated reaction conditions and reagents and theready availability of a reactive carbonyl group in most of the ABNsprepared as important reasons for widespread studies on ABNs.

According to the existing chemical literature, some derivatives of 3-ABNhave been found to possess useful biological activities. The observedbiological activies have included potent analgesic properties andantitusive activities as well as antagonism to analgesic effects andeven weak narcotic antagonism depending on the particular compoundinvolved. Some have displayed local anesthetic activity and simple 3-ABNis reportedly effective against influenza infection. Other derivativesof 3-ABN have displayed powerful ganglioplegic and hypotensiveproperties. Several have been found to be sedatives, antipyretics, andpsycholaleptic and hypoglycemic agents. Some3,7-diazabicyclo[3.3.1]nonanes possess antiarrhythmic potencies.

The Chemical Reviews article further described the subclass of3-thia-7-azabicyclo[3.3.1]nonanes as being of much less interest andidentifies a series of diphenyl and/or diaryl substituted derivatives ashaving been prepared through the Mannich reaction. In U.S. Pat. No.4,581,361 certain 3-thia-7-azabicyclo[3.3.1]nonanes and derivatives aredisclosed and claimed as antiarrhythmic compounds.

SUMMARY OF THE INVENTION

The present invention involves novel 3,7-diheterabicyclo[3.3.1]nonanescontaining more than one heteroatom such as Se, N, S and O. Inparticular the invention involves novel3-selena-7-azabicyclo[3.3.1]nonanes, corresponding nitrogen compounds,related polyheterotricyclo compounds and derivatives thereof. Thus thepresent invention provides novel 3-selena-7-azabicyclo[3.3.1]nonan-9-onecompounds having the formula: ##STR1## where Ar is: ##STR2##

The present invention also provides novel3-selena-7-azabicyclo[3.3.1]nonane compounds having the formula:##STR3## where Ar is: ##STR4##

The invention further provides the hydroperchlorate, HCl, HBr and HIsalts of the novel nonane compounds (2) and correspond salts of the9-diol and 9-dimethoxy derivatives of the selena nonanes and methylphenylamine nonanes characterized by the formula: ##STR5## where Ar is:##STR6## Z is Se, S or ##STR7## Y=--H, --OH or --OCH₃ and X is ClO₄ ⁻,Cl⁻, Br⁻ or I⁻.

In a similar manner the invention provides the 6,8-diaryl substituted,selenium and nitrogen 3,7-diheterabicyclo[3.3.1]nonanes including the9-one, 9-diol and 9-dimethoxy derivatives as well as the correspondingacid salts characterized by the formulae: ##STR8## where Ar is Ph (i.e.,##STR9## CH₂ Ph,p-H₃ CO₆ H₄ CH₂, 3,4-(H₃ CO)₂ C₆ H₂ CH₂, o-ClC₆ H₄, orp-ClC₆ H₄ ; X⁻ is ClO₄ ⁻, Cl⁻, Br⁻, or I⁻ ; Z is Se, S, O, or NCH₂ Ph;and Y is H, OH, or OCH₃.

The invention still further provides for related polyheterotricyclocompounds and corresponding derivatives thereof characterized by theformulae: ##STR10## where Ar is Ph, CH₂ Ph, o-H₃ CC₆ H₄, p-H₃ CC₆ H₄,o-H₃ COC₆ H₄, p-H₃ COC₆ H₄, o-ClC₆ H₄, or p-ClC₆ H₄ ; X⁻ is ClO₄ ⁻, Cl⁻,Br⁻, or I⁻ ; Z is Se, S, O, CHR or NR'; R is CH₃, C₂ H₅, n-C₃ H₇ or i-C₃H₇ ; and R' is H, CH₃, C₂ H₅ or C(CH₃)₃.

More specifically the invention relates to the3-selena-7-azabicyclo[3.3.1]nonane compounds and their respectivehydroperchlorate salts as used in an antiarrhythmic process.

Thus, it is an object of the present invention to provide novelcompositions that display biological activity. Fulfillment of thisobject and the presence and fulfillment of other objects will beapparent upon complete reading of the specification and claims.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The chemical compositions according to the preferred embodiments of thepresent invention are heteronuclear ring organic compounds based on the3,7-diheterabicyclo[3.3.1]nonane structure as follows: ##STR11##

Wherein the 3-position of the 9-one structure for formula (13) isselenium, but includes oxygen, nitrogen as well as selenium in the otherformulae (14), (15), and (16) and also sulfur in the 9-disubstituted offormula (16). The 7-position is an alkylated nitrogen atoms (arylsubstituted tertiary amine) and includes the acid amine salts such asthe perchlorate and halogen acid salts, preferably the hydroperchloratesalt. The disubstituted 9-position of the formula (16) is preferablyeither a 9-diol or 9-dialkyloxy structure.

The novel chemical compositions according to the preferred embodimentsof the present invention also include the 6,8-diaryl substituted3,7-diheterabicyclo[3.3.1]nonane structures as follows: ##STR12##

In these 6,8-diaryl substituted derivatives, the 3-position ispreferably selenium, sulfur, nitrogen, oxygen and carbon and includesthe endo-endo and endo-exo isomers. As in the previous formulae (13)through (16), the 9-position can be preferably unbsubstituted, 9-one,9-diol or 9,9-dimethoxy and also includes the alkylated nitrogen atom atthe 7-position and their corresponding tertiary amine acid salts(hydroperchlorate, HCl, HBr and HI).

The novel chemical compositions according to the preferred embodimentsof the present invention further includes the related polyheteratricyclocompounds based on the following structural formulae: ##STR13##

In these tricycle compounds, the hetero atoms include selenium, sulfur,oxygen and nitrogen along with either two or four alkylated nitrogenatoms as well as a tertiary amine acid salts (preferably thehydroperchlorate).

These compounds are the active ingredients for potential drugs and/orintermediates for the active ingredients of potential drugs for use inthe treatment of disorders of the heart. They display goodantiarrhythmic activity and as such are viable candidates to controlarrhythmias in humans who have suffered heart attacks or infarctions.

Typically, the 9-one and the tricyclo ether oxygen and ketone containingcompounds are synthesized by the reaction of a tetrahydroheterapyranonein the presents of an aldehyde and amine or ammonium salt according to aMannich or Mannich-type reaction. For example, and as illustrated in thefollowing reaction scheme A, 4-selenanone (17) is typically reacted withan amine such as benzylamine, 2-aminomethylthiophene, phenethylamine,p-methoxyphenethylamine, 3,4-dimethoxyphenethylamine and the like andparaformaldehyde in the presence of glacial acetic acid and methanol toproduce the 3-selena-7-azabicyclo[3.3.1]nonane-9-ones (18). The 9-one(18) is then either reduced with hydrazine hydrate in triethyleneglycol/potassium hydroxide media and then reacted directly withperchloric acid in benzene yielding the hydroperchlorate of3-selena-7-azabicyclo[3.3.1]nonanes (19) or the corresponding 9,9-diolderivatives (20) respectively. ##STR14##

In reaction scheme B, the tetrahydroheterapyranone is reacted with analdehyde in absolute ethanol and ammonium acetate to produce a mixtureof 6,8-aryl substituted 3,7-diheterabicyclo[3.3.1]nonan-9-one isomers.As specifically illustrated in scheme B using 4-selenanone (17) as thereactant, a mixture of6,8-diaryl-3-selena-7-azabicyclo]3.3.1]nonan-9-one isomers (21) and (22)are synthesized. As further illustrated and after isolation, the isomeris converted sequentially to the corresponding6,8-diaryl-3-selena-7-azabicyclo[3.3.1]nonane (23) using the reducingagent hydrazine hydrate followed by conversion to the secondary aminesalt (24); i.e., hydroperchlorate in this embodiment. ##STR15##

Reaction scheme C using 1-benzyl-4-piperidone (25) in a manner closelyanalogous to the previous reactions scheme A which used 4-selenanone asa reactant. As illustrated, the aryl amine (again benzylamine) andparaformaldehyde react in the presence of glacial acetic acid andmethanol to produce the N,N'-dibenzyl-3,7-diazabicyclo[3.3.1]nonan-9-one(26). This diazabicyclo[3.3.1]nonan-9-one (26) is then converted to oneof three derivatives by one of three separate reaction pathways. Usingperchloric acid in benzene and 3 Å molecular sieve with methanol, thehydroperchlorate amine salt of the 9,9-dimethoxy derivative (27) isproduced. The use of perchloric acid in an aqueous media produces thehydraperchlorate amine salt of the 9,9-dihydroxy derivative (28). And,in a manner analogous to the reaction scheme A, a sequential reductionusing hydrazine hydrate in triethylene glycol and potassium hydroxidefollowed by perchloric acid in benzene produces the hydroperchloratetertiary amine salt of the reduced form of the diazabicyclo[3.3.1]nonane(29). ##STR16##

In reaction scheme D, the 1-benzyl-4-piperidone (25) of scheme C isreacted with an aromatic aldehyde (ortho-chlorobenzaldehyde in thisspecifically illustrated embodiment) with ammonium acetate and absoluteethanol in a manner similar to scheme B. An isomeric mixture of the6,8-ortho-chlorobenzyl derivatives of 3,7-diazabicyclo[3.3.1]nonan-9-one(30) and (31) are produced. As further illustrated and with isomericisolation, the 9-ones (30) and (31) are converted to the corresponding6,8-bi(ortho-chlorophenyl) diazabicyclo[3.3.1]nonane (32) and (33) bythe reducing agent hydrazine hydrate. This in turn can be converted tothe isomeric mixture of the corresponding tertiary amine acid salts;i.e., hydroperchlorate salts in this illustrate (34) and (35). ##STR17##

In the closely related reaction scheme E, the generic startingtetrahydroheterapyranone (36) is reacted with an amine (benzylamine asillustrated) and paraformaldehyde in glacial acetic acid and methanol. Aresulting mixture of the dispiro[5.1.5.3]hexadecan-7-one (37) and thepyrido[3,4-e]-1,3-oxazine (38) are produced. As further suggested andafter isolation the corresponding tertiary amine acid salts (thehydroperchlorate salt (39) in this illustrated embodiment) can beproduced by the action of perchloric acid in benzene and isopropylalcohol. ##STR18##

It should be appreciated that other tetrahydroheterapyranones,arylamines and aromatic aldehydes can readily be selected as reactantsfor the Mannich or Mannich-type reactions being illustrated in thereaction schemes. Similarly, various appropriate reactants can beemployed in the selective oxidation or reduction at the 9-position asgenerally known in the art. The Mannich reaction is particularly usefulin that, as previously indicated, it does not required complicatedreaction conditions and reagents. However for purposes of the presentinvention, other methods of synthesis well known in the art should beconsidered equivalent. For example and for more detailed disclosure ofvarious alternative methods of synthesis (including the Mannichreaction) and methods of synthesis of various subsequent derivatives,the previously mentioned Chemical Reviews article by Jeyaraman et al. isagain cited and herein incorporated by reference for such purposes.Furthermore, according to the preferred embodiments of the presentinvention, the water solubility of the 3,7-hetrabicyclo[3.3.1]nonanecompounds and related heteratricyclo compounds can be advantageouslyenhanced by formation of the corresponding tertiary amine salts and thelike, prior to patient treatment.

In order to further illustrate the formation of the3,7-diheterabicyclo[3.3.1]nonanes and related compounds according to thepresent invention, the preparation and isolation of purified, watersoluble, biologically-active tertiary and secondary amine salts thereofand the antiarrhythmic activity of the compositions the followingsequence of examples are presented.

EXAMPLE I 7-Benzyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one (40)

Benzylamine (0.67 g, 6.26 mmol) and glacial acetic acid (0.38 g, 6.33mmol) were dissolved in dry methanol (30 mL). Paraformaldehyde (1.5 g,50 mmol) was added and the resulting mixture was brought to reflux underan atmosphere of nitrogen. 4-Selenanone (1.00 g, 6.13 mmol) was thenadded in one portion which quickly turned the solution yellow. Boilingwas continued under nitrogen in the dark for 5 hours. The resulting deepred solution was then allowed to cool to room temperature and wasstirred for an additional 18 hours. The methanol was evaporated(aspirator) and the orange residual oil was partitioned between ether(50 mL) and water (50 mL). The ether layer was discarded and the aqueouslayer was made basic with KOH (85%, 1.2 g 18.2 mmol). This solution wasextracted with ether (5×40 mL). The combined extracts were dried (K₂CO₃) and evaporated (aspirator) to give an oil which was digested on asteam bath with Skelly B (50 mL). Evaporation gave a light yellow oilwhich solidified upon standing. This solid was recrystallized (95%ethanol) to give 7-benzyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one (0.78g, 43%) as white needles: mp 91°-92° C.; IR (KBr) cm⁻¹ 1726 (C═O);¹ HNMR (DCCl₃) δ2.71 [m, 4H, H(1,5),H(6.8)ax], 3.08 [m, 2H, H(6,8)], 3.20[m, 4H, H(2,4)], 3.57 [s, 2H, H(11-ArCH₂)], 7.32 [m, 5H, ArH]; ¹³ C NMR(DCCl₃) ppm 25.5 [t, C(2,4)], 46.2 [d, C(1,5)], 59.0 [t, C(6,8)],61.5[t, C(11-ArCH₂)], 127.1 [d, C(4')], 128.2 (d) and 128.6 (d) [C(2',3',5',6')], 138.0 [s, C(1')], 213.8 [s, C(9)]; ¹⁵ N NMR (DCCl₃) ppm38.31 [N(7)]; ⁷⁷ Se NMR (DCCl₃) ppm 84.68 [Se(3)]. A satisfactoryelemental analysis proved very difficult for the compound and thus itwas converted to the hydroperchlorate salt without further purification.##STR19##

EXAMPLE II 7-(2-Thiophene)methyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one(41)

A solution was made of 2-aminomethylthiophene (1.39 g, 12.3 mmol) andglacial acetic acid (1.10 g, 18.3 mmol) in methanol (60 mL) in a 150 mL,three-necked, round-bottomed flask equipped with a water-cooledcondenser. To this solution was added paraformaldehyde (3.0 g, 100 mmol)and the resulting mixture was heated to reflux. 4-Selenanone (2.00 g,12.3 mmol) was added and reflux was continued for 5 hours. Afterallowing the resulting red solution to cool to room temperature, themethanol was evaporated (aspirator) to give a red oil. This oil waspartitioned between water and ether (100 mL: 30 mL). The ether portionwas discarded and the aqueous layer was made basic by the addition ofNaOH (1.5 g, 37.5 mmol). The resulting yellow suspension was extractedwith ether (5×40 mL). The combined extracts were washed with water (2×30mL) and dried (K₂ CO₃). Evaporation of the ether gave a brown oil whichwas digested in boiling Skelly B (3×100 mL). Evaporation of the Skelly Bgave 1.72 g of 7-benzyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one as acolorless viscous oil (47%): IR (film) cm⁻¹ 1710 (C═O); ¹ H NMR (CDCl₃)δ2.60-2.74 [m, 4H, H(2,4)], 3.02-3.18 [m, 4H, H(1,5), H(6,8)_(ax) ],3.27 [dd, 2H, H(6,8)_(eq), J=11.7 Hz, 3.4 Hz], 3.75 [s, 2H, H(10)],6.0-7.30 [m, 3H, ArH]; ¹³ C NMR (CDCl₃) ppm 24.8 [C(2,4)], 46.0[C(1,5)], 55.6 [C(10)], 58.5 [C(6,8)], 124.9 [C(4')], 125.5 [C(2')],126.1 [C(3')], 141.4 [C(1')], 212.9 [C(9)]; ¹⁵ N NMR (CDCl₃) ppm 40.31[N(7)]; ⁷⁷ Se NMR (CDCL₃) ppm 86.28 [Se(3)]. The compound was usedwithout further purification. ##STR20##

EXAMPLE III 7-Phenethyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one (42)

A sodium was made of phenethylamine (1.48 g, 12.3 mmol) and glacialacetic acid (0.85 g, 14.2 mmol) in methanol (60 mL). Paraformaldehyde(3.0 g, 100 mmol) was added and the resulting mixture was heated toreflux with magnetic stirring under an atmosphere of nitrogen.4-Selenanone (2.00 g, 12.3 mmol) was added and boiling was continued for5 hours resulting in an orange solution. Methanol was evaporated(aspirator) and the residual orange oil was mixed with water (200 mL).This aqueous mixture was made basic by addition of NaOH (2.0 g, 50 mmol)and was then extract with ether (5×40 mL). The combined extracts werewashed with saturated brine and dried (K₂ CO₃). Evaporation (aspirator)gave a brown residue which was digested in boiling Skelly B (150) mL).Evaporation of the Skelly B (150 mL). Evaporation of the Skelly B gave asolid which was recrystallized (ethanol) to give 0.82 g (22%) of7-phenethyl-3 -selena-7-azabicyclo[3.3.1]nonan-9-one as a light tansolid: mp 91°-92° C.; IR (KBr) cm⁻¹ 1710 (C═O); ¹ H NMR (DCCl₃ δ262-2.83[m, 8H, H(2,4,1,5,10-ArCH₂)], 3.02-3.20 [m, 6H, H(6,8,11-NCH₂)],7.16-7.38 [m, 5H, Ar-H]; ¹³ C NMR (DCCl₃) ppm 25.4 [5, C(2,4)], 33.7 [5,C(10-ArCH₂)], 46.2 [d, C(1,5)], 58.3 [5, C(11-NCH₂)], 59.1 [t, C(6,8)],125.8 [s, C(4')], 128.1 [d, C(2',6') or C(3',5')], 128.4 [d, C(3',5') orC(2',6')], 139.7 [s, C(1')], 213.5 [s, C(9 )]; ¹⁵ N NMR (DCCl₃) ppm35.44 [N(7)]; ⁷⁷ Se NMR (DCCl₃) ppm 79.51 [Se(3)]. The compound wasconverted to the hydroperchlorate salt without further purification.##STR21##

EXAMPLE IV 7-p-Methoxyphenethyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one(43)

A solution was made of p-methoxyphenethylamine (0.93 g, 6.16 mmol) andglacial acetic acid (0.50 g, 8.33 mmol) in methanol (40 mL).Paraformaldehyde (1.50 g, 50.0 mmol) was added and the resulting mixturewas heated to reflux under an atmosphere of nitrogen. 4-Selenanone 10(1.00 g, 613 mmol) was added in one portion and boiling was continuedfor 4 hours. The methanol was evaporated (aspirator) from the resultingorange solution to give a very viscous red oil. This oil was dissolvedin water (150 mL) and KOH (85%, 1.0 g, 15.2 mmol) was added to make thesolution very basic. The resulting yellow suspension was extracted withether (5×40 mL). The combined extracts were washed with water 930 mL)and dried (K₂ CO₃). Evaporator of the ether (aspirator) gave 0.72 g(35%) 7-p-methoxyphenethyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one as alight yellow oil: IR (neat) cm⁻¹ 1723 (C═O); ¹ H NMR (DCCl₃) δ2.50-2.80[m, 8H, H(1,5,2,4,10-ArCH₂)], 2.96-3.14 [m, 6H, H(6,8,11, NCH₂)], 3.71[s, 3H, OCH₃ ], 6.72-6.90 [m, 2H, H(3',5')], 7.00-7.16 [m, 2H,H(2',6')]; ¹³ C NMR (DCCl₃) ppm 24.6 [C(2,4)], 32.0 [C(10-ArCH₂)], 45.4[C(2',6')], 130.9 [C(1')], 156.9 [C(4')], 212.5 [C(9)]; ¹⁵ N NMR (DCCl₃)ppm 35.43 [N(7)]; ⁷⁷ Se NMR (DCCl₃) [Se(3)] ppm 78.81. Without furtherpurification the compound was converted to the hydroperchlorate salt.##STR22##

EXAMPLE V7-(3,4-Dimethoxy)phenethyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one (44)

A solution was made of 3,4-dimethoxyphenethylamine (2.23 g, 12.3 mmol)and glacial acetic acid (1.0 g, 16.6 mmol) in methanol (60 mL).Paraformaldehyde (3.0 g, 100 mmol) was added and the resulting mixturewas heated to boiling. 4-Selenanone (2.00 g, 12.3 mmol) was added andboiling was continued for 4 hours. The resulting brown solution wasevaporated (aspirator) to a brown oil. This oil was added to water (150mL) and the mixture which formed was extracted with ether (4×50 mL). Thecombined extracts were washed with water (30 mL) and dried (K₂ CO₃).Evaporation (aspirator) gave a dark brown oil which was digested inboiling Skelly B (3×100 mL). After decantation from a small amount ofresidual oil, evaporation of the supernatant gave 1.4 g of7-(3,4-dimethoxy)phenethyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one as apale yellow viscous oil (31%): IR (neat) cm⁻¹ 1730 (C═ O);¹ H NMR(DCCl₃) δ2.60-2.80 [m, 8H, H(2,4,1,5,10-ArCH₂)], 3.00-3.20 [m, 6H,H(6,8,11-NCH₂)], 3.80 [s, 3H, OCH₃ ], 3.84 [s, 3H, OCH₃ ], 7.70-7.90 [m,3H, ArH]; ¹³ C NMR (DCCl₃) ppm 25.4 [C(2,4)], 33.2 [C(10-ArCH₂)], 46.2[C(1,5)], 55.7 [both OCH₃ ], 58.6 [C(11-NCH₂)], 59.1 [C(6.8)], 111.3,112.0, 120.5, 132.8 [C(1')], 141.2, 148.7, 213.8 [C(9)]; ¹⁵ N NMR(DCCl₃) ppm 35.16 [N(7)]; ⁷⁷ Se NMR (DCCl₃) ppm 77.00 [Se(3)]. Withoutfurther purification the compound was converted to the hydroperchloratesalt. ##STR23##

EXAMPLE VI 7-Benzyl-3-selena-7-azabicyclo[3.3.1]nonane Hydroperchlorate(45)

A solution was made of 7-benzyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one(2.0 g, 6.8 mmol) and hydrazine (95%, 5.0 g, 148 mmol) in triethyleneglycol (40 mL). Potassium hydroxide (85%, 10.0 g, 152 mmol) was addedand the resulting mixture was heated to 140° C. in an oil bath under anitrogen atmosphere for 12 hours. After cooling to room temperature, thesolution was poured into water (200 mL) and the resulting suspension wasextracted with ether (5×40 mL). The combined extracts were driedovernight (K₂ CO₃) and cooled to 0° C. Perchloric acid (60%, 2.0 g, 11.9mmol) was added dropwise. The yellow orange solid which formed wasfiltered and recrystallized (methanol) to give7-benzyl-3-selena-7-azabicyclo[3.3.1]nonane hydroperchlorate (1.94 g,75%) as white needles: mp 161.0°-162.0° C. (dec); IR (KBr)cm⁻¹ 3440,1105; ¹ H NMR (DMSOd₆) δ1.75 [d, 1H, H(9), J=13.7 Hz], 1.88 [d, 1H,H(9), J=13.6 Hz], 2.41 [br, s, 2H(1,5)], 2.64 [d, 2H, H(2,4)_(ax),J=12.21 Hz], 3.19 [d, 2H, H(2,4)_(eq), J=12.10 Hz], 3.42 [m, 2H,H(6,8)_(ax) ], 3.61 [d, 2H, H(6,8)_(eq), J=11.83 Hz], 4.32 [d, 2H,H(10-NCH₂), J=5.75 Hz]; ¹³ C NMR (DMSO-d₆) ppm 22.0 [C(2,4)], 25.2[C(1,5)], 28.5 [C(9)], 56.6 [C(6,8)], 60.5 [C(10N-CH₂)], 128.9, 129.3,129.8, 130.0 ]ArC]; ¹⁵ N NMR (DMSO-d₆) ppm 51.56 [N(7)]; ⁷⁷ Se NMR(DMSO-d₆) ppm 96.61 [Se(3)]. Analysis calculated for C₁₄ H₂₀ C1NO₄ Se:C, 44.14; H, 5.30; N, 3.68; Cl. 9.32; Se, 20.75. Found: C, 44.45; H,5.38; N, 3.61; Cl, 9.52; Se, 20.67. ##STR24##

EXAMPLE VII 7-(2-Thiophene)methyl-3-selena-7-azabicyclo[3.3.1]nonaneHydroperchlorate (46)

7-(2-Thiophene)methyl-3-selena-7-azabicyclo[3.3.1]nonaneHydroperchlorate (1.0 g, 3.33 mmol) and anhydrous hydrazine (95%, 2.0 g,5.94 mmol) were dissolved in triethylene glycol (40 mL) in a 60 mL,jacketed flask which was equipped for distillation. Potassium hydroxide(85%, 3.0 g, 45.5 mmol) was added and the resulting mixture was heatedwith stirring to 140°-145° C. by boiling xylene in the jacket of thereaction vessel. Heating was continued for 4 hours after which time thereaction mixture was cooled to room temperature and was poured into coolwater (150 mL). The resulting suspension was extracted with ether (5×40mL) and the combined extracts were dried (K₂ CO₃). After filtration ofthe desiccant, 60% HClO₄ (1.0 g, 6.0 mmol) was added dropwise, veryslowly, causing an orange solid to form. The ether was decanted and thesolid was recrystallized twice (isopropyl alcohol, decolorizing carbon)to give 0.88 g of7-(2-Thiophene)methyl-3-selena-7-azabicyclo[3.3.1]nonanehydroperchlorate as white needles (68%): mp 141.0°-141.5° C.: IR (KBr)cm⁻¹ 3450, 1150; ¹ H NMR (DMSO-d₆) δ1.74 [d, 1H, H(9), J=13.6 Hz], 1.86[d, 1H, H(9), J=13.6 Hz], 2.43 [br s, 2H, H(1,5)], 2.64 [d, 2H,H(2,4)_(ax), J=12.0 Hz], 3.19 [d, 2H, H(2,4)_(eq), J=11.3 Hz], 3.35 [m,2H, H(6,8)_(ax) ], 3.62 [d, 2H, H(6,8)_(eq), J=12.7 Hz], 4.53 [d, 12H,H(10-NCH₂), J=5.3 Hz], 7.16 [dd, 1H, H(3'), J=5.1 Hz, 3.7 Hz], 7.36 [d,1H, H(2'), J=3.3 Hz], 7.75 [d, 1H, H(4'), J=5.1 Hz], 9.24 [br s, 1H,H(7)]; ¹³ C NMR (DMSO-d₆) ppm 21.9 [t, C(2,4)], 25.3 [d, C(1,5)], 28.6[t, C(9)], 60.5 ]t, C(10-NCH₂)], 56.2 (t, C(6,8)], 127.2 (d, C(4')],129.3 [d, C(2')], 130.5 [s, C(1')], 131.8 [d, C(3')]; ¹⁵ N NMR (DMSO-d₆)ppm 58.54 [N(7)]; ⁷⁷ Se NMR (DMSO-d₆) ppm 89.41 [Se(3)]. Analysiscalculated for C₁₂ H₁₈ C1NO₄ Se: C, 37.27; H, 4.69; N, 3.62; Se, 20.42.Found: C, 37.30; H, 4.76; N, 3.60; Se, 20.10. ##STR25##

EXAMPLE VIII 7-Phenethyl-3-selena-7-azabicyclo[3.3.1]nonaneHydroperchlorate (47)

A jacketed flask was charged with a mixture of7-phenethyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one (1.3 g, 4.2 mmol) N₂H₄ (95%, 2.0 g, 59 mmol), and KOH (85%, 6.0 g, 91 mmol) in triethyleneglycol (40 mL). The flask was equipped for simple distillation under arapid stream of nitrogen. The reaction mixture was heated to 140°-145°C. by boiling xylene contained in the jacket. Heating was continuedunder a nitrogen stream for 5 hours. During this time, a small amount ofwater and hydrazine distilled out. The resulting clear, light brownsolution was cooled in a water bath to room temperature and was thenpoured into ice-water (200 mL). The white suspension which formed wasextracted with ether (5×40 mL). The combined ether extracts were washedwith brine (30 mL) and dried (K₂ CO₃) overnight. After filtering out thedesiccant, this ether solution was cooled to 0°-5° C. in an ice bath and60% HC1O₄ (1.0 g, 6.0 mmol) was added dropwise, very slowly. Afterstirring overnight, the resulting orange precipitate was filtered andrecrystallized (methanol, decolorizing carbon) to give 0.67 g (40%) of7-Phenethyl-3-selena-7-azabicyclo[3.3.1]nonane hydroperchlorate as whiteplates: mp 249°-250° C. (dec): IR (KBr) cm⁻¹ 3400, 1140; ¹ H NMR(DMSO-d₆) δ1.73 [br d, 1H, H(9), J=14.0 Hz], 1.89 [br, d, 1H, H(9),J=13.8 Hz], 2.41 [br s, 2H, H(1,5)], 2.64 [d, 2H, H(2,4)_(ax), J=12.1Hz], 3.07 [t, 2H, H(11-ArCH₂), J=7.9 Hz], 3.20 [d, 2H, H(2,4)_(eq),J=12.2 Hz], 3.33 [ m, 4H, H(10-NCH₂), (6,8)_(ax) ], 3.86 [d, 2H,H(6,8)_(eq), J=12.3 Hz], 728-7.50 [m, 5H, Ar-H], 8.89 [br s, 1H, H(7)];¹³ C NMR (DMSO-d₆) ppm 21.9 [t, C(2,4)], 25.3 [d, C(1,5)], 28.5 [t, C(9)or C(11-ArCH₂)], 29.9 [t, C(11-ArCH₂) or C(9)], 56.7 [y, C(6,8)], 58.8[t, C(10-NCH₂)], 126.8 [d, C(4')], 128.5 [d, C(2',6',3',5')], 136.2 [s,C(1')]; ¹⁵ N NMR (DMSO-d₆) ppm 48.25 [N(7)]; ⁷⁷ Se NMR (DMSO-d₆) ppm88.42 [Se(3)]. Analysis calculated for C₁₅ H₂₂ C1NO₄ Se: C, 45.64; H,5.62; N, 3.55; Se, 20.00. Found C, 45.77; H, 5.80; N, 3.48; Se, 19.85.##STR26##

EXAMPLE IX 7-p-Methoxyphenethyl-3-selena-7-azabicyclo[3.3.1]nonaneHydroperchlorate (48)

A jacketed flask equipped for simple distillation was charged with asuspension of7-p-methoxyphenethyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one (0.65 g,1.92 mmol), hydrazine (95%, 1.00 g, 29.7 mmol), and potassium hydroxide(85%, 3.0 g, 45.5 mmol) in triethylene glycol (25 mL). Under a rapidstream of nitrogen, the suspension was heated to 140°-145° C. by boilingxylene in the jacket of the flask. Stirring was continued at thistemperature for 3 hours during which time a small amount of water andexcess hydrazine distilled from the reaction mixture. After cooling toroom temperature, the resulting solution was diluted with water (100 mL)and was extracted with ether (5×40 mL). The combined ether extracts weredried (K₂ CO₃) overnight and 60% perchloric acid (0.5 g, 3.0 mmol) wasadded very slowly. This precipitated an orange solid. The ether wasdecanted and the solid was recrystallized (absolute ethanol) with theaid of decolorizing carbon to give 0.58 g (71%)of7-p-methoxyphenethyl-3-selena-7-azabicyclo[3.3.1]nonanehydroperchlorate as white needles: mp 208.5°-209.0° C.; IR (KBr) cm⁻¹3425, 1085; ¹ H NMR (DMSO-d₆) δ1.73 [br d, 1H, H(9), J=14.0 Hz], 1.90[br, d, 1H, H(9), J=14 Hz], 2.42 [br s, 2H, H(1,5)], 2.65 [d, 2H,H(2,4)_(ax), J=12 Hz], 3.02 [t, 2H, H(11-ArCH₂)], J=7 Hz], 3.22 [d, 2H,H(2,4), J=14 Hz], 3.30 [m, 2H, H(10-NCH₂)], 3.36 [d, 2H, H(6.8)_(ax),J=12 Hz], 3.76 [s, 3H, OCH₃ ], 3.86 [d, 2H, H(6,8)_(eq), J=12 Hz], 6.97[d, 2H, H(3',5'), J=9 Hz], 7.32 [d, 2H, H(2',6'), J=9 Hz], 8.92 [br s,1H, H(7)]; ¹³ C NMR (DMSO-d₆) ppm 21.9 [t, C(2,4)], 25.3 [d, C(1,5)],28.5 [t, C(9) or C(11)], 28.9 [t, C(11-ArCH₂) or C(9)], 55.0 [q, OCH₃ ],56.7 [t, C(6,8)], 58.9 [t, C(10-NCH₂)], 114.0 [d, C(3',5')], 127.7 [s,C(1')], 129.6 [d, C(2',6')], 158.1 [s, C(4')], ¹⁵ N NMR (DMSO-d₆) ppm48.10 [N(7)]; ⁷⁷ Se NMR (DMSO-d₆) ppm 88.64 [Se(3)]. Analysis calculatedfor C₁₆ H₂₄ C1NO₅ Se: C, 45.24; H, 5.69; N, 3.30; Se, 18.59. Found: C.45.42; H, 5.80; N, 3.30; Se, 18.46. ##STR27##

EXAMPLE X 7-(3,4-Dimethoxy)phenethy-3-selena-7-azabicyclo[3.3.1]nonaneHydroperchlorate (49)

A jacketed flask which was equipped for distillation, was charged withsolution of7-(3,4-dimethoxy)phenethyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one (1.10g, 3.00 mmol), anhydrous hydrazine (95%, 200 g, 5.94 mmol), andpotassium hydroxide (85%, 3.0 g, 45.5 mmol) in triethylene glycol (40mL). This solution was heated to 140°-145° C. by boiling xylene in thejacket of the reaction flask. Heating was continued for 4 hours duringwhich time a small amount of water and excess hydrazine distilled. Thereaction mixture, which had turned brown, was cooled and poured intocool water (150 mL). The resulting suspension was extracted with ether(4×50 mL). The combined extracts were washed with water (40 mL) anddried (K₂ CO₃). Perchloric acid (60%, 1.0 g, 6.0 mmol) was added to theether solution dropwise, very slowly. This precipitated a white solidwhich rapidly turned orange. The ether was decanted and the solid wasrecrystallized twice from absolute ethanol (decolorizing carbon) to give0.92 g (68%) of7-(3,4-dimethoxy)phenethy-3-selena-7-azabicyclo[3.3.1]nonanehydroperchlorate as a white crystalline solid: mp 162°-163° C.; IR (KBr)cm⁻¹ 3450, 1090; ¹ H NMR (DMSO-d₆) δ1.74 [d, 1H, H(9), J=13 Hz], 1.92[d, 1H, H(9), J=13 Hz], 2.42 [br, s, 2H, H(1,5), 2.65 (d, 2H,H(2,4)_(ax), J=12 Hz], 3.02 [t, 2H, H(11-ArCH₂)], 3.22 [d, 2H,H(2,4)_(eq), J=12 Hz], 3.36 [n, 4H, H(10-NCH₂) and H(6,8)_(ax) ], 3.76[s, 3H, OCH₃ ], 3.80 [x, 3H, OCH₃ ], 3.87 [d, 2H, H(6,8)_(eq), J=12 Hz],6.88-7.02 [m, 3H, ArH], 8.88 [br s, 1H, H(7)]; ¹³ C NMR (DMSO-d₆) ppm22.0 [C(2,4)], 25.3 [C(1,5)], 28.5 [C(11) or C(9)], 29.4 [C(9) or C(11)ArCH₂)], 55.4 [OCH₃)], 56.7 [C(6,8)], 58.9 [C(10)-NCH₂)], 112.0, 112.3,120.6, 128.3 [C(1'), 147.7 [C(3') or C(4')], 148.8 [C(3') or C(4')], ¹⁵N NMR (DMSO-d₆) ppm 48.03 [N(7)]; ⁷⁷ Se NMR (DMSO-d₆) ppm 88.35 Se(3)].Analysis calculated for C₁₇ H₂₆ C1NO₆ Se: C, 44.90; H, 5.76; N, 3.08.Found: C, 44.86; H, 5.86; N, 3.04. ##STR28##

EXAMPLE XI 7-Benzyl-3-selena-7-azabicyclo[3.3.1]nonan-9,9-diolHydroperchlorate (50)

7-Benzyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one (0.65 g, 2.2 mmol) wasdissolved in dry benzene (250 mL). Perchloric acid (60%, 1.0 g, 6.0mmol) was added dropwise very slowly with cooling and swirling. Thisprecipitated an orange solid which adhered to the side of the flask. Thebenzene was decanted and the solid was recrystallized (95% ethanol) togive 7-benzyl-3-selena-7-azabicyclo[3.3.1]nonan-9,9-diolhydroperchlorate (0.62 g, 68.3%) as white needles: mp 214.0°-216.0° C.(dec); IR (KBr) cm⁻¹ 3430, 1080; ¹ H NMR (DMSO-d₆) δ2.43 [br s, 2H,H(2,4)_(ax) ], 2.72 [br d, 2H, H(2,4)_(eq) ], 3.22-3.50 [m, 6H,H(6,8)_(ax), H(1,5), OH], 350-3.64 [m, 2H, H(6,8)_(eq) ], 4.35 [d, 2H,H(10-NCH₂)], 740-7.70 [m, 5H, ArH], 9.20 [br s, 1H, H(7)]; ¹³ C NMR(DMSO-d₆) ppm 21.1 [C(2,4)], 34.7 [C(1,5)], 54.9 [C(6,8)], 60.1[C(10)-NCH₂)], 92.5 [C(9)], 129.2, 129.7, 130.0, 130.5 [ArC]; ¹⁵ N NMR(DMSO-d₆) ppm 51.88 [N(7)]; ⁷⁷ Se NMR (DMSO-d₆) ppm 62.39 [Se(3)].Analysis calculated for C₁₄ H₂₀ NC1SeO₆ : N, 3.39; Se, 19.13. Found: N,3.20; Se, 19.51. ##STR29##

EXAMPLE XII 6,8-Diphenyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one (51)

A jacketed flask was charged with a solution of dry ammonium acetate(2.31 g, 30.0 mmol) in absolute ethanol (30 mL) which was warmed to 65°C. by boiling methanol in the jacket. A solution of 4-selenanone (2.45g, 15.0 mmol) and benzaldehyde (3.18 g, 30.0 mmol) in absolute ethanol(15 mL) was added in one portion. The resulting solution was stirredunder nitrogen at 65° C. for 45 minutes. After cooling the reactionmixture to about 30°-40° C., ether (15 mL) was added and stirring wascontinued for 10 minutes. Cooling (5° C.) overnight resulted in theformation of a yellow solid which was filtered and recrystallized(ethanol) to give 0.89 g (17%) of6,8-diphenyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one as white needles:mp 207.0°-208.5° C. (dec); IR (KBr) cm⁻¹ 3320 (N--H), 1730 (C═O); ¹ NNMR (DCCl₃) δ1.77 [br s, 1H, H(7)], 2.84 [br d, 4H, H(2,4), J=8 Hz],3.59 [m, 2H, H(1,5)], 5.04 [m, 2H, H(6,8)], 7.20-7.50 [m, 10 H,ArH]; ¹³C NMR (DCCl₃) ppm 92.2 [C(2,4)], 54.0 [C(1,5)], 64.2 [C(6,8)], 144.4[C(1'), 127.0 [C(3',5') or C(2',6')], 127.9 [C(4')], 128.7 [C(2',6') orC(3',5')] 207.2 [C(9)]; ¹⁵ N NMR (DCCl₃) ppm 63.28 [N(7)]; ⁷⁷ Se NMR(DCCl₃) ppm 25.38 [Se(3)]. Analysis calculated for C₁₉ H₁₉ NOSe: C,64.04; H, 5.38; N, 3.93; Se, 22.17. Found: C, 63.86; H, 5.45; N, 3.81;Se, 21.90. ##STR30##

EXAMPLE XIII 6,8-Di(2-thiophene)-3-selena-7-azabicyclo[3.3.1]nonan-9-one(52)

A solution of 2-thiophenecarboxaldehyde (1.38 g, 12.3 mmol) and dryammonium acetate (0.94 g, 12.3 mmol) in absolute ethanol (20 mL) washeated to boiling on a hot plate. To this was added a hot solution offreshly sublimed 4-selenanone 10 (1.00 g, 6.13 mmol) in absolute ethanol(15 mL). Boiling was continued for 10 minutes with ethanol being addedto keep the volume constant. During this time the colorless solutionturned yellow. The flask was removed from the hot plate, was stoppered,and was allowed to stand at room temperature for 3 days. The resultingdark red solution was decanted from the yellow solid which had formedduring this time. The solid was taken up in benzene (100 mL) and wastreated with decolorized carbon. Filtration followed by evaporation(aspirator) gave a light brown solid which was recrystallized (methanol)to give 0.40 g, (18%) of6,8-Di(2-thiophene)-3-selena-7-azabicyclo[3.3.1]nonan-9-one as a lightyellow solid: mp 155°-161° C. (dec); IR (KBr) cm⁻¹ 3260 (N--H), 1723(C═O); ¹ H NMR (DCCl₃) δ2.16 [br s, 1H, H(7)], 2.80 [m, 4H, H(1,5) andH(2,4)_(ax) ], 3.57 [d, 2H, H(2,4)_(eq), J=10.03 Hz], 5.32 [d, 2H,H(6,8), J=3.96 Hz], 6.90-7.40 [m, 6H, Ar-H]; ¹³ C NMR (DCCl₃) ppm 29.3[C(2,4)], 54.6 [C(1,5)], 59.1 [C(6,8)], 123.7, 124.8, 126.3[C(2',3',4')], 147.0 [C(1')], 213.3 [C(9)]; ¹⁵ N NMR (DCCl₃) ppm 67.09[N(7)]; ⁷⁷ Se NMR (DCCl₃) ppm 30.60 [Se(3 )].

6,8-Di(2-thiophene)-3-selena-7-azabicyclo[3.3.1]nonan-9-one proveddifficult to purify in order to obtain a satisfactory elementalanalysis. Thus it was used directly in the conversion to the amine6,8-di(2-thiophene)-3-selena-7-azabicyclo[3.3.1]nonane of Example XVIwhich did lend itself to purification and was analyzed. ##STR31##

EXAMPLE XIV6,8-Di(4-chlorophenyl)-3-selena-7-azabicyclo[3.3.1]nonan-9-one (theendo,exo isomer) (53),(54)

A solution of dry ammonium acetate (0.94 g, 12.3 mmol) andp-chlorobenzaldehyde (1.73 g, 12.3 mmol) in absolute ethanol (20 mL) washeated to boiling in a 50-mL, Erlenmeyer flask on a hot plate. To thissolution was added a boiling solution of freshly sublimed 4-selenanone(1.00 g, 6.13 mmol) in absolute ethanol (15 mL). The combined solutionswere boiled for 10 min with ethanol being added to keep the volumeconstant. During this time the colorless solution became light yellow.The flask was then removed from the hot plate and stoppered. Thereaction mixture was allowed to stand at room temperature for 3 days,during which time the solution turned dark reddish-brown and a yellowsolid formed. The liquid was decanted and the solid was dissolved inbenzene (100 mL). This solution was treated with decolorizing carbon andwas filtered. Evaporation (aspirator) of the benzene gave a light brownsolid which was recrystallized (absolute ethanol) giving 0.33 g (13%) of6,8-di(4-chlorophenyl)-3-selena-7 -azabicyclo[3.3.1]nonan-9-one (theendo,exo isomer) as a light tan solid: mp 219°-220° C. (dec); IR (KBr)cm⁻¹ 3280 (N--H), 1722 (C═O); ¹ H NMR (DCCl₃) δ1.70 [br s, 1H, H(7)],2.69 [m, 4H, H(1,5) and H(2,4)_(ax) ], 3.56 [d, 2H, H(2,4)_(eq), J=10.20Hz], 4.99 [d, 2H, H(6,8), J=4.07 Hz], 7.30-7.40 [m, 8H, Ar-H]; ¹³ C NMR(DCCl₃) ppm 29.0 [C(2,4)], 53.0 [C(1,50)], 63.4 [C(6,8)], 128.2,[C(2',6') or C(3',5')], 128.8 [C(3',5') or C(2',6')], 133.7 [C(4')],142.5 [C(1')], 213.4 (9)]; ¹⁵ N NMR (DCCl₃) ppm 62.84 [N(7)]; ⁷⁷ Se NMR(DCCl₃) ppm 26.67 [Se(3)].

6,8-Di(4-chlorophenyl)-3-selena-7-azabicyclo[3.3.1]nonan-9-one (theendo,exo isomer) proved very difficult to purify for elementaryanalysis. It was converted to amine6,8-di(4-chlorophenyl)-3-selena-7-azabicyclo[3.3.1]nonane.

Addition of water (10mL) to the original mother liquor caused theprecipitation of a dense brown solid. After allowing this mixture tostand at room temperature overnight, the solid was filtered andrecrystallized (ethanol, decolorizing carbon) to give 0.2 g (7%) of6,8-di(4-chlorophenyl)-3-selena-7-azabicyclo[3.3.1]nonan-9,-one (theendo, endo isomer) as a light tan solid: mp 168°-171° C. (dec); IR (KBr)cm⁻¹ 3315 (N--H), 1710 (C═O); ¹ H NMR (CDCl₃) δ2.68-2.90 [m, 2H,H(2,4)_(ax) ], 2.83 [br s, 2H, H1,5)], 3.06-3.18 [m, 2H, H(2,4)_(eq) ],4.48 [br s, 2H, H(6,8)], 7.30-7.60 [m, 8H, ArH]; ¹³ C NMR (CDCl₃) ppm20.9 [t, C(2,4)], 51.5 [d, C(1,5)], 63.8 [ d, C(6,8)], 127.7 [d, C(2')or C(3')], 128.8 [d, C(3') or C(2')], 133.4 [s, C(4')], 137.6 [s,C(1')], 212.9 [s, C(9)]; ¹⁵ N NMR (CDCl₃) ppm 44.24 [N(7)]; ⁷⁷ Se NMR(CDCl₃) ppm 122.66 [Se(3)]. ##STR32##

EXAMPLE XV 6,8-Diphenyl-3-selena-7-azabicyclo[3.3.1]nonane (55)

6,8-Diphenyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one (0.89 g, 2.5 mmol)and hydrazine (95%, 3.0 g, 89 mmol) were dissolved in triethylene glycol(40 mL). This solution was placed in a jacketed flask equipped forsimple distillation under a rapid stream of nitrogen. Water was boiledin the jacket which heated the reaction mixture to about 100° C. Thesolution was stirred at this temperature for 2 hours. Potassiumhydroxide (85%, 1.0 g, 15 mmol) was added and the temperature wasincreased to about 208° C. by boiling tetralin in the jacket. As thetemperature increased a gas evolved, presumably nitrogen. After stirringat this temperature for 4 h, 3 mL of water and excess hydrazine haddistilled out. The reaction mixture was cooled to 60°-70° C. and wasthen poured into ice-water (200 mL). The filtered solid wasrecrystallized (ether, decolorized carbon) to give 0.63 g (74%) of amine6,8 -diphenyl-3-selena-7-azabicyclo[3.3.1]nonane as white needles: mp193.5°-195.0° C. (dec); IR (KBr) cm⁻¹ 3250 (N--H); ¹ H NMR (C₆ D₆) δ0.83[dt, 1H, H(9), J=12.0, 1.5 Hz], 1.34 [m, 1H, H(7)], 1.78 [m, 2H,H(1,5)], 2.00 [dd, 2H, H(2,4)_(ax), J=12.0, 1.4 Hz], 2.33 [m, 1H, H(9)],2.84 [dd, 2H, H(2,4)_(eq), J=12.0, 2.0 Hz], 4.34 [d, 2H, H(6,8), J=2.0Hz], 7.1-7.4 [m, 10H, ArH]; ¹³ C NMR (D₆ D₆ @50° C.) ppm 25.1 [C(2,4)],27.2 [C(9)], 34.5 [C(1,5)] , 62.0 [C(6,8)], 126.9 [C,(2') or C(3')],127.2 [C(4')], 128.7 [C(3') or C(2')], 151.9 [C(1')]; ¹⁵ N NMR (C₆ D₆)ppm 55.68 [N(7)]; ⁷⁷ Se NMR (C₆ D₆ @50° C.) ppm 2.38 [Se(3)]. Analysiscalculated for C₁₉ H₂₁ NSe: C, 66.66; H, 6.18; N, 4.09; Se, 23.06.Found: C, 66.82; H, 6.34; N, 3.97; Se, 22.82. ##STR33##

EXAMPLE XVI 6,8-Di(2-thiophene)-3-selena-7-azabicyclo[3.3.1]nonane (56)

6,8-Di(2-thiophene)-3-selena-7-azabicyclo[3.3.1]nonan-9-one (1.00 g,2.71 mmol) and anhydrous hydrazine (95%, 1.0 g, 30 mmol) were dissolvedin triethylene glycol (40 mL) which was contained in a jacketed flaskequipped for distillation. By boiling water in the jacket, the reactionmixture was heated to 100° C. and stirred at this temperature for 2hours. Potassium hydroxide (85%, 2.0 g, 30 mmol) was added in oneportion and the water in the jacket then replaced by xylene which, whenboiled, brought the temperature of the reaction mixture to 140°-145° C.Stirring was continued at this temperature for 5 hours. After cooling toroom temperature, the reaction mixture was poured into ice-cold water(200 mL) after which a precipitate immediately formed. This mixture wasset aside at room temperature overnight and was then filtered. Thefiltrate was taken up in boiling benzene and treated with decoloringcarbon. The benzene was evaporated (aspirator) and the residue wasrecrystallized in 95% ethanol to give 0.64 g (67%) of6,8-di(2-thiophene)-3-selena-7-azabicyclo[3.3.1]nonane as a light tansolid: mp 183°-185° C. (dec); IR (KBr) cm⁻¹ 3270 (N--H); ¹ H NMR (DCCl₃)δ1.28 [d, 1H, H(9), J=13 Hz, 2 Hz], 1.78 [br s, 1H, H(7)], 2.18 [br s,2H, H(1,5)], 2.32 [d, 2H, H(2,4)_(ax), J=12 Hz], 2.50 [m, 1H, H(9)],3.20 [dd, 2H, H(2,4)_(eq), J=13 Hz], 4.79 [d, 2H, H(6,8), J=4 Hz], 6.96[dd, 2H, ArH]; 7.01 [2H, d, ArH], 7.21 [d, 2H, ArH] ; ¹³ C NMR (DCCl₃)ppm 25.0 [C(2,4)], 25.8 [C(9)], 34.6 [C(1,5)], 57.1 [C(6,8)], 122.2[C,(4'), 122.6 [C(2')], 126.1 [C(3')]; 150.7 [C(1')]; ¹⁵ N NMR (DCCl₃)ppm 60.10 [N(7)]; ⁷⁷ Se NMR (DCCl₃) ppm 4.05 [Se(3)].6,8-Di(2-thiophene)-3-selena-7-azabicyclo[3.3.1]nonane proved difficultto purify for satisfactory analysis and was converted to6,8-Diphenyl-3-selena-7-azabicyclo[3.3.1]-nonane Hydroperchlorate ofExample XIX. ##STR34##

EXAMPLE XVII 6,8-Di(4-chlorophenyl)-3-selena-7-azabicyclo[3.3.1]nonane(57)

Endo, exo 6,8-di(4-chlorophenyl)-3-selena-7-azabicyclo[3.3.1]nonan-9-one(the endo, exo isomer) (2.00 g, 4.71 mmol), anhydrous hydrazine (95%,2.0 g, 60 mmol), and triethylene glycol (35 mL) were placed in ajacketed, round-bottomed flask along with a magnetic stirring bar. Thecontents of the flask were heated to 100° C. under a stream of nitrogenby boiling water in the jacket of the reaction flask. Stirring at thistemperature was continued for 3 hours after which time potassiumhydroxide (85%, 5.0 g, 76 mmol) was added in one portion. The reactionmixture was then heated to 140°-145° C. by boiling xylene in the jacket.After 4 hours at this temperature, the resulting solution was cooled(60°-70° C.) and was poured into water (100 mL) which precipitated acream-colored solid. This solid was filtered and washed with water.Recrystallization (twice, absolute ethanol, decolorizing carbon) gave6,8-di(4-chlorophenyl)-3-selena-7 -azabicyclo[3.3.1]nonane as a lighttan solid (0.91 g, 47%): mp 179°-180° C. (dec); IR (KBr) cm⁻¹ 3260(N--H); ¹ H NMR (DCCl₃) δ1.30 [d, 1H, H(7), J=12 Hz], 1.74 [br s, 1H,H(7)], 2.04 ]br s, 2H, H(1,5)], 2.28 [br d, 2H, H(2,4)_(ax), J=12 Hz],2.48 [m, 1H, H(9)], 3.17 [dd, 2H, H(2,4)_(eq), J=12 Hz, 4 Hz], 4.43 [d,2H, H(6,8), J=5 Hz], 7.26-7.50 [m, 8H, ArH]; ¹³ C NMR (DCCl₃) ppm 25.1[C(2,4)], 26.9 [C(9)], 33.8 [C(1,5 )], 60.9 [C(6,8)], 127.9, 128.6,132.6 [C(4')], 145.7 [C(1')], ¹⁵ N NMR (DCCl₃) ppm 55.37 [N(7)]; ⁷⁷ SeNMR (DCCl₃) ppm -0.79 [Se(3)].

6,8-Di(4-chlorophenyl)-3-selena-7-azabicyclo[3.3.1]nonane provedexceedingly difficult to obtain in pure form and give a satisfactoryanalysis. Thus, it was converted to the hydroperchlorate salt6,8-di(4-chlorophenyl)-3-selena-7-azabicyclo[3.3.1]nonanehydroperchlorate of Example XXI which analyzed well. ##STR35##

EXAMPLE XVIII 6,8-Di(4-chlorophenyl)-3-selena-7-azabicyclo[3.3.1]nonane(58)

Endo, endo6,8-di(4-chlorophenyl)-3-selena-7-azabicyclo[3.3.1]nonan-9-one (theendo, exo isomer) (2.00 g, 4.71 mmol), anhydrous hydrazine (95%, 2.0 g,60 mmol), and triethylene glycol (35 mL) were placed in a 60-mL,two-necked, jacketed, round-bottomed flask along with a magneticstirring bar. This mixture was heated to 100° C. by boiling water in thejacket of the reaction flask. Stirring at this temperature under astream of nitrogen was continued for 2 hours at which time potassiumhydroxide (85%, 5.0 g, 76 mmol) was added. The temperature of theresulting mixture was increased to 140°-145° C. by boiling xylene in thejacket of the reaction flask. After stirring at this temperature for 3h, the resulting solution was cooled (60°-70° C. and was poured intowater (100 mL). This precipitated a light yellow solid which wasfiltered and washed with water. This solid was recrystallized (absoluteethanol, decolorizing carbon) to give6,8-di(4-chlorophenyl)-3-selena-7-azabicyclo[3.3.1]nonane as a whitepowder (1.14 g, 59%): mp 163°-165° C. (dec); IR (KBr) cm⁻¹ 3290 (N--H);¹ H NMR (CDCl₃) δ2.04 [br s, 2H, H(1,5)], 2.18 [d, 1H(9)]; J=14 Hz],2.25 [d, 2H, H(2,4)_(ax), J=12 Hz], 2.36 [d, 1H, H(9), J=13 Hz], 2.59[br s, 1H, H(7)], 3.04 [dd, 2H, H(2,4)_(eq), J=12 H, 4 Hz], 4.50 [d, 2H,H(6,8), J=3 Hz], 7.32-7.52 [m, 8H, ArH]; ¹³ C NMR (CDCL₃) pmm 17.7[C(2,4)], 30.4 [C(1,5)], 35.0 [C(9)], 64.0 [C(6,8)], 127.9, 128.5, 132.6[C(4')], 141.1 [C(1')]; ¹⁵ N NMR (CDCL₃) ppm 50.52 [N(7)]; ⁷⁷ Se NMR(CDCl₃) ppm 101.86 Se(3)]. ##STR36##

EXAMPLE XIX 6,8-Diphenyl-3-selena-7-azabicyclo[3.3.1]nonaneHydroperchlorate (59)

A solution was made of 6,8-diphenyl-3-selena-7-azabicyclo[3.3.1]nonane(0.63 g, 1.8 mmol) in benzene (100 mL). Perchloric acid (60%, 1.0 g, 6.0mmol) was added dropwise, very slowly with swirling. The resultingmixture was allowed to stand at room temperature with occasionalswirling for 3 hours. The orange solid which formed was filtered andrecrystallized (methanol) to give 0.62 g (78%) of6,8-diphenyl-3-selena-7-azabicyclo[3.3.1]nonane hydroperchlorate aswhite needles: mp 288.0°-289.0° C. (dec, sealed tube); ¹ H NMR (DMSO-d₆)δ1.78 [br d, 1H, H(9), J=13.0 Hz], 2.36 [br d, 2H, H(2,4)_(ax), J=13.0Hz], 2.59 [m, 3H, H(1,5) and H(9)], 3.16 [dd, 2H, H(2,4)_(eq), J=12.0,2.0 Hz], 4.73 [br d, 2H, H(6,8), J=3.0 Hz], 7.19-7.70 [m, 10H, ArH],8.72 [m, 1H, H(7)_(ax) ], 9.67 [m, 1H, H(7)_(eq) ]; ¹³ C NMR (DMSO-d₆)ppm 23.5 [C(2,4)], 26.6 [C(9)], 31.2 [C(1,5)], 61.5 [C(6,8)], 128.5,128.7, 128.6, 137.0 [C(1')]; ¹⁵ N NMR (DMSO-d₆) ppm 57.91 [N(7)]; ⁷⁷ SeNMR (DMSO-d₆) ppm 1.16 [Se(3)]. Analysis calculated for C₁₉ H₂₂ ClNO₄Se: C, 51.54; H, 5.01; N, 3.16; Se, 17.83. Found: C, 51.52; H, 4.94; N,3.34; Se, 17.65. ##STR37##

EXAMPLE XX 6,8-Di(2-thiophenyl-3-selena-7-azabicyclo[3.3.1]nonaneHydroperchlorate (60)

A solution was made of6,8-di(2-thiophenyl-3-selena-7-azabicyclo[3.3.1]nonane (0.5 g, 1.4 mmol)in benzene (200 mL) and isopropyl alcohol (10 mL). To this solution wasadded 60% HClO₄ (0.5 g, 3.0 mmol) dropwise slowly causing a whiteprecipitate to form. This precipitate quickly became yellow. The solventwas decanted and the solid was recrystallized twice (isopropyl alcohol,decolorized carbon) to give 0.4 g (63%) of6,8-di(2-thiophenyl)-3-selena-7-azabicyclo[3.3.1]nonane hydroperchlorateas white needles: mp 285° C. (dec); ¹ H NMR (DMSO-d₆) δ1.78 [d, 1H,H(9), J=14 Hz], 2.36 [d, 2H, H(2,4)_(ax), J=14 Hz], 2.44 [m, 1H, H(9)],2.66 [br s, 2H, H(1,5)], 3.19 [dd, 2H, H(2,4).sub. eq, J=12 Hz, 3 Hz],5.07 [m, 2H, H(6,8), 7.16 [dd, 2H, H(3'), J=4 Hz, J=6 Hz], 7.43 [d, 2H,H(2'), J=4 Hz], 7.69 [dd, 2H, H(4'), J=3 Hz, J=6 Hz], 9.36 [br s, 1H,H(7)], 9.61 [br s, 1H, H(7)]; ¹³ C NMR (DMSO-d₆) ppm 23.5 [C(2,4)], 26.2[C(9)], 32.5 [C(1,5))], 56.1 [C(6,8)], 127.3 [C(2') of C(4')], 127.6[C(4') or C(2')], 129.2 [C(3')], 138.9 [C(1')]; .sup. 15 N NMR (DMSO-d₆)ppm 62.39 [N(7)]; ⁷⁷ Se NMR (DMSO-d₆) ppm 5.11 [Se(3)]. Analysiscalculated for C₁₅ H₁₈ ClNO₄ S₂ Se: C, 39.61; H, 3.99; N, 3.08; S,14.10; Se, 17.36. Found: C, 39.81; H, 3.97; N, 3.10; S, 14.35; Se,17.18. ##STR38##

EXAMPLE XXI 6,8-Di(4-chlorophenyl)-3-selena-7-azabicyclo[3.3.1]nonaneHydroperchlorate (61)

6,8-Di(4-chlorophenyl)-3-selena-7-azabicyclo[3.3.1]nonane (1.00 g, 2.43mmol) was dissolved in ether (200 mL). Perchloric acid (60%), 1.0 g, 6.0mmol) was added slowly with vigorous swirling. The resulting mixture wasallowed to stand for 24 hours with occasional swirling. Theyellow-orange solid which formed was filtered and recrystallized (twice,absolute ethanol, decolorizing carbon) to give6,8-di(4-chlorophenyl)-3-selena-7-azabicyclo[3.3.1]nonanehydroperchlorate as a white powder (0.46 g, 37%): mp 272°-274° C. (dec);¹ H NMR (DMSO-d₆) δ1.77 [d, 1H, H(9), J=12.0 Hz], 2.36 [d, 2H,H(2,4)_(ax), J=10.8 Hz], 2.53 [m, 2H, H(1,5)], 3.14 [d, 2H, H(2,4)_(eq),J=10.5 Hz, 3.38 Hz], [br s, 1H, H(9'), 4.76 [br s, 2H, H(6,8)],7.50-7.75 [m, 8H, ArH], 8.77 [br s, 1H, H(7)], 9.59 [br s, 1H, H(7)]; ¹³C NMR (DMSO-d₆) ppm 23.5 [C(2,4)], 26.5 [C(9)], 31.1 [C(1,5))], 60.6[C(6,8)], 128.5, 130.9, 133.8 [C(4')], 136.1 [C(1'); ¹⁵ N NMR (DMSO-d₆)ppm 57.67 [N(7)]; ⁷⁷ Se NMR (DMSO-d₆) ppm 2.25 [Se(3)]. Analysiscalculated for C₁₉ H₂₀ Cl₃ NO₄ Se: C, 44.60; H, 3.94; N, 2.47. Found: C,44.53; H, 3.84; N, 2.74. ##STR39##

EXAMPLE XXII 6,8-Di(2-chlorophenyl)-3-selena-7-azabicyclo[3.3.1]nonaneHydroperchlorate (62)

6,8-Di(4-chlorophenyl)-3-selena-7-azabicyclo[3.3.1]nonane (1.00 g, 2.43mmol) was dissolved in ether (200 mL) in a 500 mL, round-bottomed flask.Perchloric acid (60%, 1.0 g, 6.0 mmol) was added slowly with swirling.The resulting mixture was allowed to stand at room temperature for 24hours with occasional swirling. The orange solid which formed wasfiltered and recrystallized (absolute ethanol, decolorizing carbon) togive 6,8-di(2-chlorophenyl)-3-selena-7-azabicyclo[3.3.1nonanehydroperchlorate (0.36 g, 29%) as white needles: mp 264°-265° C. (dec);¹ H NMR (DMSO-d₆) δ2.16 [d, 1H, H(9), J=12.1 Hz], 2.29 [d, 2H,H(2,4)_(ax), J=12.7 Hz], 2.50 [m, 3H, H(1,5), H(9)], 3.13 [d, 2H,H(2,4)_(eq), J=12.3 Hz, 5.07 [d, 2H, H(6,8), J=8.5 Hz], 7.58-7.90 [m,8H, ArH], 9.18 [br s, 1H, H(7)], 10.46 [br s, 1H, H(7)]; ¹³ C NMR(DMSO-d₆) ppm 17.7 [C(2,4)], 29.7 [C(1.5)], 32.0 [C(9)], 63.7 [C(6,8)],128.6, 128.9, 133.2 [C(4')], 134.5 [C(1')]; ¹⁵ N NMR DMSO-d₆) ppm 49.57[N(7); ⁷⁷ Se NMR (DMSO-d₆) ppm 74.96 [Se(3)]. Analysis calculated forC₁₉ H₂₀ Cl₃ NO₄ Se.C₂ H₅ OH: C, 45.22; H, 4.70; N, 2.51; Se, 14.16.Found: C, 44.93; H, 4.39; N, 2.58; Se, 14.43. ##STR40##

EXAMPLE XXIII N,N'-Dibenzyl-3,7-diazabicyclo[3.3.1]nonan-9-one (63)

Following a procedure similar to that disclosed in U.S. Pat. No.3,962,449, a three-necked, 50-mL, round-bottomed flask was fitted with adropping funnel (60 mL), a condenser with an N₂ inlet, a heating mantle,and a magnetic stirrer. This flask was charged with a solution ofbenzylamine (2.68 g, 25.0 mmol) and glacial acetic acid (1.54 g, 25.8mmol) in methanol (25 mL). To this solution was added paraformaldehyde(1.58 g, 52.5 mmol); then the apparatus was flushed with N₂ and themixture was brought to reflux with stirring. After 15 min, a solution of1-benzyl-4-piperidone (4.73 g, 25.0 mmol) and glacial acetic acid (1.50g, 25.0 mmol) in methanol (18 mL) was added over 0.5 hours. Theresulting orange solution was then boiled at reflux for an additional9.5 hours. The mixture was then cooled to room temperature and thesolvent was evaporated (aspirator) to give an orange oil. Water (50 mL)and KOH pellets (85%, 3.30 g, 50.0 mmol) were added, and the resultingoily, orange suspension was extracted (CH₂ Cl₂, 3×50 mL). The organicextracts were combined and dried (MgSO₄, overnight). Filtration of themixture followed by evaporation (aspirator) afforded an orange oil whichwas vacuum distilled (8×10⁻⁷ mm Hg, diffusion pump). At 106°-108° C.there was collected a colorless oil (0.36 g), the ¹³ C NMR of which wasidentical to 1-benzyl-4-piperdone. A second fraction (bp 180°-205° C.)was collected as a yellow oil but with substantial decomposition of theresidue. This second fraction was redistilled (180°-185° C., 1.0 ×10⁻⁶mm Hg) to yield again a yellow oil. This oil was dissolved in hot SkellyB (80 mL) and, upon cooling to -10° C., pureN,N'-dibenzyl-3,7-diazabicyclo[3.3.1]nonan-9-one (2.53 g, 31.6%) wasprecipitated as a while solid: mp 61°-63° C. (literature 70°-71° C. Thecompound was used in the next step without further purification. Thespectroscopic data for this compound were: IR (KBr) cm⁻¹ 2963, 2822,1738, 1721, 748, 703 ¹ H NMR (DCCl₃) δ2.52 [br s, 2H, H(1,5)], 2.77,2.78 [two d, J=10.7 Hz, 4H, H(2,4,6,8)ax], 3.00 [br d, J=10.5 Hz, 4H,H(2,4,6,8)eq], 3.53 [s, 4H, ArCH₂ ], 7.23-7.30 [m, 10H, ArH]; ¹³ C NMR(DCCl₃) ppm 46.7 [d, C(1,5)], 58.01 [t, C(2,4,6,8)], 61.1 [t, ArCH₂ ],126.90 [d, p-ArC], 128.02 [d, o- or m-ArC], 128.53 [d, m- or o-ArC]138.02 [s, i-ArC], 214.0 [s, C(9)]; ¹⁵ N NMR (DCCl₃) ppm 39.25 [N(3,7)].

EXAMPLE XXIV N,N'-Dibenzyl-3,7-diazabicyclo[3.3.1]nonan-9-one (63)

In a minor modification of the previous procedure, a solution of1-benzyl-4-piperidone (4.73 g, 25.0 mmol) and glacial acetic acid (1.50g, 25.0 mmol) in methanol (25 mL) was added as before to a boilingmixture of paraformaldehyde (6.00 g, 200 mmol), glacial acetic acid(1.62 g, 27.0 mmol), benzylamine (2.68 g, 25.0 mmol), and methanol (100mL). The reaction time was 24 hours and the aqueous workup was asdescribed previously. Instead of the distillation described, the crudeoil from the workup was then digested in Skelly B (300 mL) on a steambath for 0.5 hours. The hot supernatant was decanted from the yellowresidue and evaporated (aspirator followed by vacuum pump, roomtemperature 0.02 mm Hg, 20 min). This affordedN,N'-dibenzyl-3,7-diazabicyclo[3.3.1]nonan-9-one (6.84 g, 85.4%) as awhite oil that did not solidify after 3 days at -10° C. The ¹ H and ¹³ CNMR spectra of this oil were virtually identical to that described forthe ketone produced in Example XXIII via method A and the materialproved to be satisfactory for use in the following Examples XXV andXXVI. ##STR41##

EXAMPLE XXV N,N'-Dibenzyl-3,7-diazabicyclo[3.3.1]nonane Hydroperchlorate(64)

Following a procedure similar to that disclosed in U.S. Pat. No.3,962,449, for the synthesis ofN,N'-dibenzyl-3,7-diazabicyclo[3.3.1]nonane, a jacketed two-necked,70-mL flask was fitted with a lower take-off condenser with an N₂ inletand a receiving flask, a thermometer, a condenser on the jacket, amagnetic stirrer, and a heating mantle. This flask was charged withN,N'-dibenzyl-3.7-diazabicyclo[3.3.1]nonan-9-one (2.00 g, 6.24 mmol),hydrazine hydrate (85%, 1.10 g, 18.7 mmol), KOH pellets (85%, 2.06 g,31.2 mmol), and triethylene glycol (25 mL). The apparatus was flushedwith N₂, and the mixture heated at 120° C. for 0.5 hours using tetralin(bp 207° C.) in the jacket. The reaction mixture was then allowed toboil at reflux for 5 hours. The temperature slowly increased to 207° C.with removal of the volatile distillates and with the evolution of N₂.The reaction mixture was cooled to room temperature and was poured,along with the distillate, into cool water (30 mL), which resulted inthe formation of a white suspension. This was extracted (ether, 4×30mL), and the combined extracts were washed successively with NaOHsolution (10%, 30 mL), H₂ O (30 mL), and NaCl solution (saturated, 30mL). After drying (Na₂ SO₄, overnight), the solution was filtered andevaporated (aspirator) to give the crude amine,N,N'-dibenzyl-3,7-diazabicyclo[3.3.1]nonane as a yellow oil (1.34 g,70.1%). This oil was dissolved in C₆ H₆ (20 mL) and treated dropwiseover 15 min with a solution of HClO₄ (60%, 2.20 g, 13.1 mmol) in2-propanol (5 mL) to give a dark solution. This solution was stirred(magnetic) for 1 hour after which it was concentrated (5 mL). Additionof ether (20 mL) precipitated the salt as a dark brown solid. Filtrationand recrystallization (aqueous ethanol, 20 mL, decolorizing carbon)afforded a first crop of N,N'-dibenzyl-3,7-diazabicyclo[3.3.1]nonanehydroperchlorate (0.652 g) as the monoperchlorate; mp 221°-222° C.Concentration of the mother liquor to 7 mL gave a second crop (0.126 g,total: 0.778 g, 43.7% total), mp 220°-222° C. The spectroscopic data forthis compound were: IR (KBr) cm⁻¹ 2960, 2841 (C--H), 2800-2600 (N⁺ --H),1100, 1080 (Cl--O); ¹ H NMR (DMSO-d₆) δ1.72 [br s, 2H, H(9)], 2.14 [brs, 2H, H(1,5)], 2.77 [d, J=13 Hz, 4H, H(2,4,6,8)]ax], 3.13 [d, J=13 Hz,4H, H(2,4,6,8)eq], 3.43 ]br s, 1H, N⁺ --H], 3.86 [s, 4H, ArCH₂ ], 7.30-7.48 [m, 10H, ArH]; ¹³ C NMR (DMSO-d₆) ppm 27.4 [d, C(1,5)], 29.54 [t,C(9)], 56.97 [t, C(2,4,6,8)], 60.4 [t, ArCH₂ ], 128.2 [d, p-ArC], 128.4[d,o- or m-ArC], 129.6 [d, m- or o-ArC], 133.30 [s, i-ArC]; ¹⁵ NMR(DMSO-d₆) ppm 54.59 [N(3,7)]. Analysis calculated for C₂₁ H₂₇ ClN₂ O₄ :C, 61.99; H, 6.69; Cl, 8.71; N, 6.88. Found: C, 61.92; H, 6.84; Cl,8.71, N, 6.82. [Although the N,N'-dibenzyl-3,7-diazabicyclo[3.3.1]nonanehydroperchlorate was supposedly synthesized (see Ruenitz, P. C. andSmissman, E. E. J. Heterocy. Chem. 1976, 13, 1111), the material was nota true pure compound since it has a melting range of 210°-217° C. andorange crystals were reported; therefore, the above data is for thetrue, pure compound)] ##STR42##

EXAMPLE XXVI N,N'-Dibenzyl-9,9-dimethoxy-3,7-diazabicyclo[3.3.1]nonaneHydroperchlorate (65)

A one-necked, 100-mL, round-bottomed flask was equipped with a Soxhletcontaining 3A molecular sieve (30 g), a condenser with N₂ inlet, amagnetic stirrer and a heating mantle. The effective cycling volume ofthe Soxhlet was approximately 20 mL. The flask was charged with asolution of N,N'-dibenzyl-3,7-diazabicyclo[3.3.1]nonan-9-one (1.00 g,3.12 mmol) in CH₃ OH (25 mL) and C₆ H₆ (25 mL) to which was added HClO₄(60%, 1.50 g, 8.96 mmol) in one portion. The volume of the methanol usedwas such that the perchloric acid always remained in solution and didnot become completely dry. The apparatus was flushed with N₂ and thecolorless solution was heated to reflux with cycling through theSoxhlet. After 24 h, the now pale yellow solution was cooled to roomtemperature and concentrated to about 15 mL. Upon standing for a fewminutes, a product precipitated as a white solid which was filtered,washed with C.sub. 6 H₆ (10 mL), and recrystallized (CH₃ OH, 80 mL) toafford the monoperchlorateN,N'-dibenzyl-9,9-dimethoxy-3,7-diazabicyclo[3.3.1]nonanehydroperchlorate (0.9103 g) as small white crystals, mp 223.6°-224.0° C.(dec). The mother liquor was concentrated to approximately 10 mL. Uponcooling at -10° C. overnight, a second crop ofN,N'-dibenzyl-9,9-dimethoxy-3,7-diazabicyclo[3.3.1]nonanehydroperchlorate was obtained (89.4 mg, total: 0.9997 g, 68.6% total),mp 219°-220° C. (dec). The spectral data were as follows: IR (KBr) cm⁻¹2800-2600 (N⁺ --H), 1100 (Cl--O); ¹ H NMR (DMSO-d₆) δ2.35 [br s, 2H,H(1,5)], 2.90 [d, J=13 Hz, 4H, H(2,4,6,8)ax], 3.08 [d, J=13, 4H,H(2,4,6,8)eq], 3.14 [s, 6H, CH₃ O], 3.88 [s, 4H, ArCH₂ ], 7.38-7.54 [m,10H, ArH], 9.84 [br s, 1H, N⁺ --H]; ¹³ C-NMR (DMSO-d₆) ppm 33.0 [d,C(1,5)], 46.96 [q, CH₃ O], 53.8 [t, C(2,4,6,8)], 59.56 [t, ArCH₂ ],95.36 [s, C(9)], 128.22 [d, p-ArC], 128.4 [d, o- or m-ArC], 129.62 [d,m- or o-ArC], 133.45 [s, i-ArC]; ¹⁵ n NMR DMSO-d₆) ppm 52.89 [N(3,7)].Analysis calculated for C₂₃ H₃₁ ClN₂ O₆ : C, 59.16; H, 6.69; Cl, 7.59;N, 6.00. Found: C, 58.98; H, 6.81; Cl, 7.86; N, 6.28. ##STR43##

EXAMPLE XXVII 7-Benzyl-9,9-dimethoxy-3-thia-7-azabicyclo[3.3.1]nonaneHydroperchlorate (66)

A one-necked, 100 mL, round-bottomed flask was fitted with a Soxhletcontaining 3A molecular sieve (30 g), a condenser, an N₂ inlet, aheating mantle, a magnetic stirrer, and a heating mantle. The effectivecycling volume of the Soxhlet was approximately 15 mL. The flask wascharged with a solution ofN-benzyl-3-thia-7-azabicyclo[3.3.1]nonan-9-one [1.00 g, 4.04 mmol) inmethanol (20 mL) and benzene (20 mL). To this solution was added HClO₄(60%, 2.03 g, 12.1 mmol) in one portion. The volume of the methanol usedwas such that the perchloric acid always remained in solution and didnot become completely dry. The apparatus was flushed with N₂ and thepale yellow solution was heated at reflux with stirring and cyclingthrough the Soxhlet for 24 hours. The solution was cooled to roomtemperature and concentrated to about 5 mL. Ether (20 mL) was added,thus precipitating the salt as a powder. This was filtered, washed withether (5 mL), and dissolved in hot methanol (20 mL, decolorizingcarbon). Trituration with ether (25 mL), followed by standing for 24 h,afforded 7-benzyl-9,9-dimethoxy-3-thia-7-azabicyclo[3.3.1]nonanehydroperchlorate (0.7345 g, 46.2%) as small white crystals: mp 193°-194°C. (dec); IR (KBr) cm⁻¹ 2800-2600 (N⁺ --H), 1090 (Cl--O); ¹ H NMR(DMSO-d₆) δ2.58 [br s, 2H, H(1,5)], 2.75 [d, J=14 Hz, 2H, H(2,4)ax],3.15-3.18 [m, 8H, H(2,4)eq,CH₃ O], 3.38 [dd or br t, J=12 Hz, 2H,H(6,8)ax], 3.60 [d, J=12 Hz, H(6,8)eq], 4.33 [d, J=5 Hz, 2H, ArCH₂ ],7.49-7.62 [m, 5 H, ArH], 9.28 [br s, 1H, N⁺ --H]; ¹³ C NMR (DMSO-d₆) ppm28.78 [t, C(2,4)], 32.20 [d, C(1,5)], 46.60 [q, CH₃ O], 47.00 [q, CH₃O], 54.42 [t, C(6,8)], 60.24 ]t, ArCH₂ ], 95.1 [s, C(9)], 129.0 [d, o-or m-ArC], 129.46 [s, i-ArC], 130.1 [d, p-ArC], 130.2 [d, m- or o-ArC];¹⁵ N NMR (DMSO-d₆) ppm 53.49 [N(7)]. Analysis calculated for C₂₆ H₂₄ClCO₆ : C, 48.79; H, 6.14; Cl, 9.00; N, 3.56; S, 8.14. Found: C, 48.73;H, 6.09; Cl, 9.39; N, 3.54; S, 8.40. ##STR44##

EXAMPLE XXVIII endo, exo- and endo,endo-7-Benzyl-2,4-bis(2-chlorophenyl)-3,7-diazabicyclo[3.3.1]nonan-9-ones(67),(68)

A three-necked, 50 mL, round-bottomed flask was fitted with a condenser,an addition funnel, a thermometer, magnetic stirrer, a heating mantle,and an N₂ inlet. This flask was charged ammonium acetate (NH₄ OAc, 2.31g, 30.0 mmol) and ethanol (10 mL) and the flask flushed with N₂. Theslurry was warmed to 40° C. with stirring until all NH₄ OAc dissolved,then the solution was cooled to room temperature. A solution of2-chlorobenzaldehyde (5.67 g, 40.3 mmol), 1-benzyl-4-piperidone (3.78 g,20.0 mmol), and deoxygenated ethanol (15 mL) was added in one portion.The resulting solution was slowly warmed to 70° C. over 30 minutes. Uponcooling to room temperature, a white precipitate (solid A) formed whichwas filtered and washed with dry ether (20 mL). These washings werecombined with the original filtrate and this solution was cooled at -10°C. for 1 hour to give a second solid precipitate (solid B) which wasalso filtered and set aside. Evaporation of the filtrate afforded anoily orange solid which was dissolved in ether (10 mL). Upon standingfor 1 hour at -10° C., a third white solid (solid C) precipitated. Thistoo was filtered and set aside. Upon standing for 24 h, a fourth whitesolid (solid D) was precipitated, which was also filtered and set aside.Upon standing for 22 days at -10° C., a small amount of a fifth solid(solid E) precipitated which was treated as before.

Solid A was recrystallized (2-propanol/HCCl₃, 3:1, 40 mL) to afford pureendo,exo-3-7-benzyl-2,4-bis(2chlorophenyl)-3,7-diazabicyclo[3.3.1]nonan-9-one(1.06 g) as long white needles: mp 184°-185° C. IR (KBr) cm⁻¹ 3340(N--H), 1733 (C═O); ¹ H NMR (DCCl₃) d 1.61 [s, 1H, N--H], 2.54, 2.56[overlapping d, J=12 Hz, and br s, 4H, H(1,5) and H(6,8)ax], 3.49 [d,J=12 Hz, 2H, H(6.8)eq], 3.73 [s, 2H, ArCH₂ ], 5.50 [br s, 2H, H(2,4)],7.14-7.80 [m, 13H, ArH]; ¹³ C NMR (DCCl₃) ppm 55.15 [d, C(1,5)], 58.77[t, C(6,8)], 59.02 [d, C(2,4)] , 60.99 [t, ArCH₂ ], 127.35, 127.48,128.38, 128.44, 128.59, 129.16, 129.21, 132.15, 138.35, 142.63 [ArC],211.95 [s, C(9)]; ¹⁵ N NMR (DCCl₃) ppm 38.31 [N(7)], 58.24 [N(3)].

Solids B, C and E were combined and recrystallized (2-propanol/HCCl₃,3:1, 15 mL) to afford additional endo,exo-3-7-benzyl-2,4-bis(2-chlorophenyl)-3,7-diazabicyclo[3.3.1]nonan-9-one(0.50 g, total: 1.56 g, 17.3%) mp 184°-185° C. Solid D was alsorecrystallized from the same solvent system (15 mL) to afford endo,endo-7-benzyl-2,4-bis(2-chlorophenyl)-3,7-diazacyclo[3.3.1]nonan-9-one(0.36 g, 4.0%) as short white needles: mp 209.5°-210.0° C.; IR (KBr)cm⁻¹ 3270 (N--H), 1717 (C═O); ¹ H NMR (DCCl₃) δ2.54 [d, J=12 Hz, 2H,H(6,8)ax], 2.76 [br s, 2H, H(1,5)], 3.12 [d, J=12 Hz, 2H, H(6,8)eq],3.32 [s, 2H, ArCH₂ ], 4.70 [br s, 1H, N--H], 4.80 [br s, 2H, H(2,4)],7.15-7.60 [m,ArH]; ¹³ C NMR (DCCl₃) ppm 50.90 [d, C(1,5)], 55.50 [t,C(6,8)], 62.11 [d, C(2,4)], 62.54 [t, ArCH₂ ], 126.62, 127.44, 128.45,128.57, 129.75, 129.81, 129.90, 132.32, 136.66, 137.22 [ArC], 212.22 [s,C(9 )]; ¹⁵ N NMR (DCCl₃) ppm 46.90 [N(7)], 54.45 [N(3)]. Analysiscalculated for the endo, exo- isomer C₂₆ H₂₄ Cl₂ N₂ O: C, 69.18; H,5.36; Cl, 15.71; N, 6.21. Found: C, 69.31, H, 5.20; Cl, 15.83; N, 6.18.Analysis calculated for the endo,endo-7-benzyl-2,4-bis(2-chlorophenyl)-3,7-diazabicyclo[3.3.1]nonan-9-oneof 17 Calcd. for C₂₆ H₂₄ Cl₂ N₂ O: C, 69.18; H, 5.36; Cl, 15.71; N,6.21. Found: C, 69.33; H, 5.53; Cl, 15.97; N, 6.09. ##STR45##

EXAMPLE XXIXendo,exo-7-Benzyl-2,4-bis(2-chlorophenyl)-3,7-diazabicyclo[3.3.1]nonan-9-one(67)

A one-necked, 50mL, round-bottom flask was fitted with a condenser, amagnetic stirrer, and an N₂ inlet at the top of the condenser. The flaskwas charged with 95% ethanol (50 mL) and the apparatus was flushed withN₂. This solvent was heated at reflux for 0.5 hours. Upon cooling toroom temperature, 1-benzyl-4-piperidone (4.73 g, 25.0 mmol),2-chlorobenzaldehyde (7.03 g, 50.0 mmol), and ammonium acetate (5.78 g,75.0 mmol) were added to the flask. The apparatus was again flushed withN₂ and the mixture was allowed to stir at room temperature. The NH₄ OAcslowly dissolved over 1 hour and the formation of a small amount ofwhite precipitate was noted shortly thereafter. Continued stirring atroom temperature for 5 days gave additional white precipitate while thesupernatant slowly developed a bright red-orange color. The precipitate(solid A) was filtered and washed with ether (50 mL). The washings werecombined with the original filtrate. This solution was cooled at -10° C.for 2 days, thus precipitating additional white solid (solid B) whichwas filtered and washed with ether. The filtrate was evaporated(aspirator) to give an orange gum. Ether (100 mL) was added and themixture was heated on a steam bath until a third, almost white solidseparated from the orange supernatant. This was filtered, washed withether and recrystallized (2-propanol/HCCl₃, 3:1, 10 mL) to affordendo,endo-7-benzyl-2,4-bis(2-chlorophenyl)-3,7-diazabicyclo[3.3.1]nonane(0.1983 g, 1.8%) as tiny needles, mp 207°-209° C.

Solid A was recrystallized (2-propanol/HCCl₃, 3:1, 110 mL) to afford(3.14 g) as long white needles, mp 184.0°-184.5° C. Solid B wasrecrystallized in the same solvent system (15 mL) to giveendo,exo-7-benzyl-2,4-bis(2-chlorophenyl)-3,7-diazabicyclo[3.3.1nonan-9-one(0.40 g, total: 3.54 g, 31.3%), mp 184°-185° C. The IR, ¹ H and ¹³ C NMRspectra for these products were identical to those given previously.

EXAMPLE XXXendo,exo-7-Benzyl-2,4-bis(2-chlorophenyl)-3,7-diazabicyclo[3.3.1]nonane(69)

A two-necked, jacketed flask with an N₂ inlet was fitted with athermometer, a lower take-off condenser, a magnetic stirrer, a heatingmantle, and a condenser on the jacket. The flask was charged withendo,exo-7-benzyl-2,4-bis(2-chlorophenyl)-3,7-diazabicyclo[3.3.1]nonan-9-one(0.80 g, 1.8 mmol) and triethylene glycol (50 mL), and the jacketcharged with tetralin (bp 207°). The apparatus was flushed with N₂ andwarmed to 110° C. with stirring to dissolve the ketone. To this solutionwas added in one portion hydrazine hydrate (85%, 0.52 g, 10.4 mmol), andthe resulting solution was stirred at 110 ° C. for 1 hour. Potassiumhydroxide pellets (85%, 5.00 g) were then added. The mixture was heatedto 195° C. over 4.5 hours until N₂ evolution ceased, with the continuousdistillation of volatiles. Upon cooling to room temperature, the tansolution was poured into H₂ O (50 mL), and the resulting suspension wasextracted with ethyl ether (5×30 mL). The combined ether extracts werewashed with NaOH solution (10%, 50 mL) and dried (Na₂ SO₄, overnight).Filtration followed by evaporation (aspirator) of the filtrate affordeda yellow oil which was dissolved in hot ethanol (25 mL). Upon cooling,the product precipitated as white plates which were filtered and driedto affordexo,exo-7-benzyl-2,9-bis(2-chlorophenyl)-3,7-azabicyclo[3.3.1]nonane(0.54 g, 69%): mp 136.4°-137.0° C.; IR (KBr) cm⁻¹ 3300 (N--H); ¹ H NMR(DCCl₃) δ1.07 [dt, J=12.3, 2.7 Hz, 1H, H(9)endo], 1.18 [br s, 1H, N--H],1.83 [br s, 2H, H(1,5)], 2.09 [d, J=10 Hz, 2H, H(6,8)ax], 2.35 [d,J=12.3 Hz, 1H, H(9)exo], 3.08 [ d, J=10 Hz, 2H, H(6,8)ax], 3.50 [s, 2H,ArCH₂ ], 4.77 [d, J=2.5 Hz, 2H, H(2,4)], 7.09-7.92 [m, 13H, ArH]; ¹³ CNMR (DCCl₃) ppm 24.55 [b, C(9)], 36.13 [d, C(1,5)], 56.08 [d, C(2,4)],58.76 [t, C(6,8)], 62.85 [t, ArCH₂ ], 126.79, 126.97, 127.52, 128.02,128.08, 129.14, 129.27, 132.38, 139.19, 145.66 [ArC]; ¹⁵ N NMR (DCCl₃)ppm 38.15 [N(7)], 50.48 [N(3). Analysis calculated for C₂₆ H₂₆ N₂ Cl₂ ;C, 71.39; H, 6.00; N, 6.40; CL, 16.21. Found: C, 71.17; H, 6.25; N,6.32; Cl, 16.15. ##STR46##

endo,endo-7-Benzyl-2,4-bis(2-chlorophenyl)-3,7-diazabicyclo[3.3.1]nonane(70)

A jacketed two-necked flask with an N₂ inlet was fitted with athermometer, a lower take-off condenser with receiving flask, a magneticstirrer, a heating mantle, and a condenser on the jacket. This flask wascharged withendo,endo-7-benzyl-2,4-bis(2-chlorophenyl)-3,7-diazabicyclo[3.3.1]nonane(1.87 g, 4.15 mmol) and triethylene glycol (75 mL) and the jacketcharged with tetralin. The apparatus was flushed with N₂, and themixture was heated to 110° C. with stirring to dissolve the ketone.Hydrazine hydrate (85%, 1.22 g, 20.7 mmol) was added in one portion andthe resulting solution was heated at 110°-120° C. for 1 hour. Potassiumhydroxide pellets (85%, 8.8 g) were then added and the resulting mixturewas heated to 195° C. over 4 hours with the distillation of volatilesand the evolution of N₂. After cooling to room temperature, the solutionwas poured into H₂ O (50 mL) and the resulting suspension was extractedwith ether (7×50 mL). The combined ether extracts were washed with NaOHsolution (10%, 100 mL) and dried (K₂ CO₃, overnight). Filtration,followed by evaporation (aspirator), of the filtrate gave a yellow oilwhich was dissolved in warm ethanol (50 mL). Trituration with etherafforded, upon cooling, white cubic crystals which were filtered, washedwith ether, and dried to give endo,endo-7-benzyl-2,4-bis(2-chlorophenyl)-3,7-diazabicyclo[3.3.1]nonane(1.11 g, 61%): mp 149°-151° C.; IR (KBr) cm⁻¹ 3250 (N--H); ¹ H NMR(DCCl₃) δ2.04 [br s, 2H, H(1,5)], 2.06 [d, J=10 Hz, 1H, H(9)], 2.17 [d,J=10 Hz, 2H, H(6,8)ax], 2.29 [d, J=10 Hz, 1H, H(9)], 2.82 [d, J=10 Hz,2H, H(6,8)eq] , 3.10 [s, 2H, ArCH₂ ], 4.44 [br s, 1H, N--H], 4.68 [br s,2H, H(2,4)], 7.08-7.44 [m, 13H, ArH]; ¹³ C NMR (DCCl₃) ppm 31.50 [d,C(1,5)], 35.87 [t, C(9)], 54.86 [t, C(6,8)], 61.63 [d, C(2,4)], 64.31[t, ArCH₂ ], 126.46, 127.33, 127.54, 128.25, 129.34, 129.80, 132.34,138.04, 140.20 [ArC]; ¹⁵ N NMR (DCCl₃) ppm 47.43 [N(7)], 53.80 [N(3)].Analysis calculated for C₂₆ H₂₆ Cl₂ N₂ : C, 71.39; H, 6.00; Cl, 16.21;N, 6.40. Found: C, 71.48; H, 6.04; Cl, 16.00; H, 6.65. ##STR47##

EXAMPLE XXXIIendo,exo-7-Benzyl-2,4-bis(2-chlorophenyl)-3,7-diazabicyclo[3.3.1]nonaneHydroperchlorate (71)

In a one-necked, 100-mL, round-bottomed flask, a solution ofendo,exo-7-benzyl-2,4-bis(2-chlorophenyl)-3,7-diazabicyclo[3.3.1]nonane(0.80 g, 1.83 mmol) in C₆ H₆ (30 mL) was treated dropwise slowly with asolution of HCLO₄ (60%, 1.50 g, 8.96 mmol) in 2-propanol (5 mL) whichresulted in the formation of a white powdery precipitate. The flask wasfitted with a condenser, and the mixture was heated on a steam bath for15 min. After cooling to room temperature, the precipitate was filteredand recrystallized in a minimum amount of 70% acetone to afford themonohydroperchlorateendo,exo-7-benzyl-2,4-bis(2-chlorophenyl)-3,7-diazabicyclo[3.3.1]nonanehydroperchlorate as fine white crystals: mp 246°-247° C. (dec): IR (KBr)cm⁻¹ 3330 (N--H), 2900-2600 (N⁺ --H), 1110 (Cl--O); ¹ H NMR (DMSO-d₆)δ1.70 [d, J=14 Hz, 1H, H(9)endo], 2.33 [d, J=11 Hz, 2H, H(6,8)ax], 2.38]br s, 2H, H(1.5)], 2.51 [overlapping d, J=14 Hz, H(9)exo and br s,DMSO], 2.85 [d, J=11 Hz, 2H, H(6,8)eq], 3.70 [s, 2H, ArCH₂ ], 5.00 [d,J=8 Hz, H(2,4)], 7.32-7.94 [m, 13H, ArH], 8.10 [br s, 1H, N--H], 9.84 brs, 1H, N⁺ --H]; ¹³ C NMR (DMSO-d₆) ppm 24.54 [t, C(9)], 33.70 [d,C(1,5)], 55.94 [t, C(6,8)], 56.85 [d, C(2,4)], 60.93 [t, C(10)],127.55-130.88 [m, ArC], 132.63, 135.51, 137.09 [ArC]; ¹⁵ NMR (DMSO-d₆)ppm 38.30 [N(7)], 54.60 [N(3)]. Analysis calculated for C₂₆ H₂₇ Cl₃ N₂ :C, 58.06; H, 5.06; Cl, 19.78; N, 5.21. Found: C, 58.16; H, 5.20; Cl,19.65; N, 5.16. ##STR48##

EXAMPLE XXXIII endo,endo-7-Benzyl-2,4-bis(2-chlorophenyl)-3,7-diazabicyclo[3.3.1.]nonaneHydroperchlorate (72)

In a one-necked, 100-mL, round-bottomed flask, a solution of endo,endo-7-benzyl-2,4-bis(2-chlorophenyl)-3,7-diazabicyclo[3.3.1]nonane(0.4957 g, 1.14 mmol) in C₆ H₆ (20 mL) was treated dropwise over 15minutes with HClO₄ (60%, 0.5 mL) with vigorous stirring. This resultedin the precipitation of a white solid. The flask was fitted with acondenser and heated on a steam bath for an additional 5 minutes,followed by cooling to room temperature. The solution was filtered andthe cloudy filtrate set aside. Recrystallization of this solid (CH₃ OH,30 mL) afforded the monoperchlorate endo,endo-7-benzyl-2,4-bis(2-chlorophenyl)-3,7-diazabicyclo[3.3.1]nonanehydroperchlorate (0.1050 g) as white crystals, mp 264.0°-264.5° C.(dec.) The cloudy benzene filtrate was evaporated to about 2 mL, and theresulting oil was dissolved in hot CH₃ OH (30 mL). Upon cooling to RT,additional salt precipitated as a white powder which was filtered andrecrystallized (CH.sub. 3 OH, 65 mL) to afford additional endo,endo-7-benzyl-2,4-bis(2-chlorophenyl)-3,7-diazabicyclo[3.3.1]nonanehydroperchlorate (0.3575 g, 74% total) as white crystals, mp 260°-262°C. (dec). The spectroscopic data were as follows: IR (KBr) cm⁻¹ 3300(N--H), 2850-2700 (N⁺ --H), 1090 (Cl--O); ¹ H NMR (DMSO-d₆) δ2.19 [d,J=12 Hz, 1H, H(9)], 2.35 [d, =12 Hz, 1H, H(9)], 2.38 [br s, 2H, H(1,5)],3.02 [br s, 4H, H(6,8)ax and eq], 4.08 [br s, 2H, ArCH₂ ], 4.88 [br s,2H, H(2,4), 5.63 [br s, 1H, N--H], 7.36-7.72 [m, 13, ArH], 10.14 [br s,1H, N⁺ --H]; ¹³ C NMR (DMSO-d₆) ppm 29.77 [d, C(1,5)], 31.39 [t, C(9)],52.97 [t, C(6,8], 60.30 [t, ArCH₂ ], 60.84 [d, C(2,4)], 127.33, 127.40,128.92, 129.26, 129.89, 130.83, 131.18, 131.33, 136.33, 142.05, [ArC];¹⁵ N NMR (DMSO-d₆) ppm 50.05 [N(7)], 52.56 [N(3)]. Analysis calculatedfor C₂₆ H₂₇ Cl₃ N₂ O₄ : C, 58.05; H, 5.07; Cl, 19.73; N, 5.21. Found: C,58.07; H, 5.08; Cl, 19.66; N, 5.27. ##STR49##

EXAMPLE XXXIV3,6-Dibenzylhexahydro-8a-methoxy-5H-4a,8-(methanothiomethano)-2H-pyrido[3,4-e]-1,3-oxazineand2,4,10,12-Tetrabenzyl-2,4,10,12-tetraaza-15-thia-dispiro[5.1.5.3]hexadecan-7-one(73),(74)

A three-necked, 50-mL, round-bottomed flask was fitted with a condenser,an N₂ inlet, a magnetic stirrer, and a heating mantle. This flask wascharged with paraformaldehyde (1.20 g, 40.0 mmol), benzylamine (1.07 g,10.0 mmol), glacial acetic acid (0.66 g, 11.0 mmol), and methanol (20mL). The apparatus was flushed with N₂ and the mixture boiled at refluxwith stirring for 15 minutes. To the mixture was added in one portion asolution of 4-thianone (0.58 g, 5.0 mmol) in methanol (10 mL) and theresulting mixture was heated at reflux for 9 hours during which theparaformaldehyde slowly dissolved and the solution turned yellow. Thesolution was then cooled to room temperature and allowed to stir anadditional 10 hours. Evaporation afforded a yellow oil which waspartitioned between ethyl ether (50 mL) and water 50 mL). The layerswere separated and the pale yellow ether layer was allowed to stand for24 hours at -10 ° C. A white crystalline solid precipitated from thisethereal solution. This was filtered and set aside. The filtrate wasconcentrated (aspirator) to half of the previous volume and allowed tostand for 3 hours. A second crop of the white solid was precipitatedwhich was filtered, combined with the first crop, and recrystallized(95% ethanol, 30 mL) to afford3,6-dibenzylhexahydro-8a-methoxy-5H-4a,8-(methanothiomethano)-2H-pyrido[3,4-e]-1,3-oxazine(0.93 g, 45%) as white needles: mp 147.2°-148.8° C.; IR (KBr) cm⁻¹ 3030,2940, 2830, 1365, 1358, 1104, 1067, 740, 704; ¹ H, NMR (DCCl₃) δ2.08 [d,J=12 Hz, 1H, H(5)ax], 2.13 [br s, 1H, H(8)], 2.37 [d, J=12 Hz, 1H,H(5)eq], 2.54 [dd, J=12, 2 Hz, 1H, H(9)ax], 2.62 [d, J= 11 Hz, 1H, ArCH₂], 2.74 [d, J=10 Hz, 1H, H(4)ax], 2.95 [d, J=10 Hz, 1H, H(4)eq], 3.22[s, 3H, CH₃ O], 3.25 [d, J=1 H, H(11)eq], 3.31 [d, J=13 Hz, 1H, H(7)ax],3.39 [dd, J=12, 2 Hz, 1H, H(9)eq], 3.49 [d, J=11 Hz, 1H, ArCH₂ ], 3.50[d, J=13 Hz, 1H, H(7)eq], 3.55 [d, J=13 Hz, 2H, ArCH₂ ], 4.02 ]d, J=8Hz, 1H, H(2)ax], 4.18 [d, J=8 Hz 1H, H(2)eq], 7.22-7.38 [m, 8H, ArH],7.58 [d, J=8 Hz, 2H, ArH]; ¹³ C NMR (DCCl₃) ppm 30.09 [t, C(9)], 33.42[d, C(8)], 34.56 [t, C(11)], 37.40 [s, C(4a)], 46.27 [q, CH₃ O], 55.38[t, C(4)], 55.79 [t, C(5)], 57.32 [t, C(7)], 59.94 [t, ArCH₂ ], 62.59[t, ArCH₂ ], 78.72 [t, C(2)], 96.93 [s, C(8a)], 126.48 [d, p-ArC],127.10 [d, p-ArC], 128.15, 128.30, 128.33, 128.53, [o- and m-ArC],137.49 [s, i-ArC], 139.66 [s, i-ArC]; ¹⁵ N NMR (DCCl₃) ppm 46.42 [N(3)],35.92 [N(3)].

In a separate experiment under slightly different conditions a secondproduct was also isolated. A three necked, 50 mL, round-bottomed flaskwas fitted with a dropping addition funnel, a condenser with an N₂inlet, a heating mantle, a magnetic stirrer, and a stopper on the thirdneck. The flask was charged with a slurry of paraformaldehyde (1.20 g,40.0 mmol) in methanol (20 mL) and was heated at reflux under N₂ withstirring (magnetic) for 15 minutes. To this boiling mixture was addeddropwise over 3.5 hours a solution of 4-thianone (0.58 g, 5.0 mmol),benzylamine (1.07 g, 10.0 mmol), glacial acetic acid (0.66 g, 11.0 mmol)in methanol (10 mL). During the addition the paraformaldehyde slowlydissolved and the solution turned to an orange-red color. The solutionwas heated at reflux for an additional 3.5 hours, and then allowed tostir at room temperature for 48 hours. A white solid precipitated fromthe now pink solution. This solid was filtered, washed with methanol (5mL) and recrystallized (2-propanol, 30 mL) to afford2,4,10,12-tetrabenzyl-2,4,10,12-tetraaza-15-thia-dispiro[5.1.5.3]hexadecan-7-one(0.261 g, 8.5% relative to the amount of benzylamine used) as whiteneedles: mp 172.5°-173.5° C.; IR (KBr) cm⁻¹ 3065, 3030, 2950, 2920,2895, 2830, 2800, 1680 (C═O), 1500, 1457, 1097, 748, 736, 703; ¹ H NMR(DCCl₃) δ2.17 [d, J=10.8 Hz, 4H, H(1,5,9,13)ax], 2.50 [d, J=8.8 Hz, 2H,H(3,11)ax], 2.77 [d, J=10.8 Hz, 4H H(1,5,9,13)eq], 3.15 [s, 4H,H(14,16)], 3.33 [d, J=13.0 Hz, 4H, ArCH₂ ], 3.49 [d, J=13.0 Hz, 4H,ArCH], 3.62 [d, J=8.8 Hz, 2H, H(3,11)], 7.20-7.30 [m, 20H, ArH]; ¹³ CNMR (DCCl₃) ppm 36.43 [t, C(14,16)], 51.26 [s, C(6,8)], 57.63 [t,C(1,5,9,13)], 59.57 [t, ArCH₂ ], 76.58 [t, C(3,11)], 127.06 [d, p-ArC],128.19 [d, o- or m-ArC], 128.55 [d, m- or o-ArC], 137.77 [s, i-ArC],211.73 [s, C(7)]; ¹⁵ N NMR (DCCl₃) ppm 43.06 [N(2,4,10,12)].

The reaction mixture filtrate was evaporated (aspirator) to anorange-red oil which was partitioned between ether (50 mL) and water (50mL). The ether layer was treated as before to afford afterrecrystallization (ethanol, 25 mL)3,6-Dibenzylhexahydro-8a-methoxy-5H-4a,8-(methanothiomethano)-2H-pyrido-[3,4-e]-1,3-oxazine(0.212 g, 11%), mp 146.5°-148.0° C.; the ¹³ C NMR spectrum of which wasidentical to that given previously. The pink aqueous suspension was madealkaline by the addition of NaOH pellets (0.50 g, 12.5 mmol) to give ayellow suspension. This suspension was extracted with ether (4×50 mL)and the combined ether extracts were dried (Na₂ SO₄, overnight). The dryethereal solution was filtered and evaporated (aspirator) and theresulting yellow oil was digested in boiling Skelly B (200 mL) for 30minutes. The hot supernatant was decanted from the brown residue andevaporated (aspirator) followed by vaccuum pump) to leave a pale yellowoil. The ¹³ C NMR (DCCl₃) of this oil indicated that is was mostlyN-benzyl-3-thia-7-azabicyclo[3.3.1]nonan-9-one (0.59 g, approximatelywith a small amount of3,6-Dibenzylhexahydro-8a-methoxy-5H-4a,8-(methanothiomethano)-2H-pyrido-[3,4-e]-1,3-oxazinepresent as an impurity. Analysis calculated for3,6-dibenzylhexahydro-8a-methoxy-5H-4a,8-(methanothiomethano)-2H-pyrido-[3,4-e]-1,3-oxazine C₂₄ H₃₀ N₂ O₂ S: C, 70.21; H, 7.37; N,6.82; S, 7.81. Found: C, 69.99; H, 7.51; N, 6.64; S, 7.97. Analysiscalculated for2,4,10,12-tetrabenzyl-2,4,10,12-tetraaza-15-thiadispiro[5.1.5.3]hexadecan-7-oneC₃₉ H₄₄ N₄ SO: C, 75.94; H, 7.19; N, 9.08; S, 5.20. Found: C, 75.73; H,7.33; N, 9.10; S, 5.20. ##STR50##

EXAMPLE XXXV3,6-Dibenzylhexahydro-8a-methoxy-5H-4a,8-(methanoselenomethano)-2H-pyrido[3,4-e]-1,3-oxazineand2,4,10,12-tetrabenzyl-2,4,10,12-tetraaza-15-selenadispiro[5.1.5.3]hexadecan-7-one(75),(76)

A three-necked, 50-mL, round-bottomed flask was equipped with acondenser, an N₂ inlet, a heating mantle, and a magnetic stirrer. Theflask was charged with benzylamine (0.67 g, 6.2 mmol), glacial aceticacid (0.38 g, 6.3 mmol), paraformaldehyde (1.50 g, 50.0 mmol), andmethanol (30 mL). The apparatus was flushed with N₂ and the mixture washeated to reflux with stirring. After 0.5 hours, the mixture was cooledto room temperature and 4-selenanone [0.75 g, 4.6 mmol] was added in oneportion. The mixture was again heated at reflux for 5 hours during whichall solids dissolved and the resulting solution turned yellow. Thesolution was then cooled to room temperature and allowed to stirovernight. The solvent was evaporated (aspirator) to leave a yellow oilwhich was partitioned between water (50 mL) and ether (50mL). The layerswere separated and the ether layer was allowed to stand for two days atroom temperature during which a white solid precipitate formed in thissolution. This was filtered and recrystallized (95% ethanol, 25 mL) toafford3,6-dibenzylhexahydro-8a-methoxy-5H-4a,8-(methanoselenomethano)-2H-pyrido[3,4-e]-1,3-oxazine(0.250 g) as white needles: mp 160.0°-160.5° C.

The aqueous layer was cooled (ice bath) and was made alkaline by theaddition of KOH pellets (85%, 1.20 g, 21.4 mmol). The resultingsuspension was extracted (ether, 5×40 mL) and the combined extracts weredried (K₂ CO₃, overnight). Filtration, followed by evaporation(aspirator), afforded a yellow oil which was digested in hexanes (50 mL)for 0.5 hours on a steam bath. The hot supernatant was decanted andevaporated to give another yellow oil. This was dissolved in hot 96%ethanol (10 mL) which, upon cooling, precipitated additional3,6-dibenzylhexahydro-8a-methoxy-5H-4a,8-(methanoselenomethano)-2H-pyrido[3,4-e]-1,3-oxazine(67.0 mg, total: 0.317 g, 22%) mp 159°-160° C.

The spectroscopic data for3,6-dibenzylhexahydro-8a-methoxy-5H-4a,8-(methanoselenomethano)-2H-pyrido[3,4-e]-1,3-oxazinewere: IR (KBr) cm⁻¹ 2840, 1370, 1362, 1108, 1062, 1055, 762, 706; ¹ HNMR (DCCl₃) δ2.09 [br s, 1H, H(8)], 2.11 [d, J=11 Hz, 1H, H(5)ax], 2.13[d, J=12 Hz, 1H, H(11)ax], 2.37 [d, J=11 Hz, 1H, H(5)eq], 2.53 [d, J=11Hz, 1H, H(9)ax], 2.58 [d, J=11 Hz, 1H, ArCH₂ ], 2.72 [d, J=11 Hz, 1H,H(4)ax], 2.93 [d, J=11 Hz, 1H, H(4)eq], 3.25 [s, 3H, CH₃ O], 3.29 [d,J=12 Hz, 1H, H(11)eq], 3.29 [d, J=14 Hz, 1H, H(7)ax], 3.44 [d, J=11 Hz,1H, ArCH₂ ], 3.47 [d, J=11 Hz, 1H, H(9)eq], 3.51 [d, J=14 Hz, 1H,H(7)eq], 3.53 [d, J=4 Hz, 2H, ArCH₂ ], 3.97 [d, J=8 Hz, 1H, H(2)ax],4.21 [d, J=8 Hz, 1H, H(2)ax], 7.26-7.64 [m, 10H, ArH]; ¹³ C NMR (DCCl₃)ppm 20.11 [t, C(9)], 25.13 [t, C(11)], 33.22 [d, C(8)], 36.84 [s,C(4a)], 46.51 [q, CH₃ O], 56.13 [t, C(4)], 56.67 [t, C(5)], 57.26 [t,C(7)], 60.55 [t, ArCH₂ ], 62.63 [t, ArCH₂ ], 78.76 [t, C(2)], 97.68 [s,C(8a)], 126.47 (d), 127.09 (d), 128.11 (d), 128.27 (d), 128.47 (d),128.52 (d), 137.43 (s), 139.57 (s), [ArC]; ¹⁵ N NMR (DCCl₃) ppm 36.20[N(12)], 47.00 [N(3)]; ⁷⁷ Se NMR ppm 126.55 [Se(8)].

In a separate experiment two other products were also isolated. Athree-necked, 50 mL, round-bottomed flask was fitted with a condenser,an N₂ inlet, a heating mantle, a magnetic stirrer, and two stoppers. Theflask was charged with a solution of benzylamine (1.07 g, 10.0 mmol),glacial acetic acid (0.62 g, 10.3 mmol), paraformaldehyde (1.20 g, 40.0mmol), and methanol (25 mL). The apparatus was flushed with N₂ and themixture heated at reflux with stirring for 15 min. 4-Selenanone (0.83 g,5.0 mmol) was then added in one position and the mixture heated atreflux for 5 hours. The supernatant turned yellow upon addition of4-selenanone. With continued heating, the paraformaldehyde slowlydissolved and the solution turned to a pink color. After about 3 hours,the formation of a white precipitate was noted. The reaction mixture wascooled to room temperature and stirred an additional 13 hours. The whitesolid was filtered from the reaction mixture, washed with methanol (5mL) and recrystallized (95% 2-propanol, 20 mL) to give2,4,10,12-tetrabenzyl-2,4,10,12-tetraaza-15-selenadispiro[5.1.5.3]hexadecan-7-one(57.6 mg. 1.9%) as white crystals: mp 165°-166° C.; IR (KBr) cm⁻¹ 3062,3032, 2910, 2820, 2792, 1675, 1494, 1453, 1086, 1068, 741, 729, 697; ¹ HNMR (DCCl₃) δ2.28 [d, J=11.2 Hz, 4H, H(1,5,9,13)ax], 2.55 [d, J=8.1 Hz,2H, H(3,11)ax], 2.77 [d, J=11.2 Hz, 4H, H(1,5,9,13)eq], 3.17 [s, 4H,H(14,16)], 3.34 [d, J=13.5 Hz, 4H, ArCH₂ ], 3.50 [d, J=13.5 [Hz, 4H,ArCH₂ ], 3.54 [d, J=8.1 Hz, 2H, H(3,11)eq], 7.20-7.30 [m, 20H, ArH]; ¹³C NMR (DCCl₃) ppm 26.67 [t, C(14,15)], 51.12 [s, C(6,8)], 58.35 [t,C(1,5,9,13)], 59.58 [T, ArCH₂ ], 126.93 [d, p-ArC], 128.05 [d, o- orm-ArC], 128.46 [d, m- or o-ArC], 137.67 [s, i-ArC], 211.80 [s, C(7)]; ¹⁵N NMR (DCCl₃) ppm 43.57.

The reaction mixture filtrate was evaporated (aspirator) to leave a pinkoil which was partitioned between ether (50 mL) and water (50 mL). Thecolorless ether layer was separated and treated as before to affordafter recrystallization3,6-dibenzylhexahydro-8a-methoxy-5H-4a,8-(methanoselenomethano)-2H-pyrido[3,4-e]-1,3-oxazine(0.2030 g, 8.8%), mp 159°-160° C., the IR and ¹³ C NMR spectra of whichwere identical to that given previously. The pink aqueous suspensionfrom the partitioning was made alkaline by the addition of KOH pellets(85%, 200 g, 30.3 mmol) to give an oily yellow suspension. Thissuspension was extracted with ether (5×40 mL) and the combined extractsdried (K₂ CO₃, overnight). The ethereal extracts were then filtered andevaporated to leave an orange oil which was digested in boiling hexanes(50 mL) for 30 min. The hot supernatant was decanted and evaporated togive a yellow oil. This was dissolved in hot 95% ethanol (30 mL),decolorized with carbon, and evaporated to 10 mL. Upon standing at -10°C. for 1 day, white needles precipitated. These were filtered and airdried to afford 7-benzyl- 3-selena-7-azabicyclo[3.3.1]nonan-9-one (0.38g, 25.8%), mp 91°-92° C. Analysis calculated for3,6-dibenzylhexahydro-8a-methoxy-5H-4a,8-(methanoselenomethano)-2H-pyrido[3,4-e]-1,3-oxazineC₂₄ H₃₀ N₂ O₂ Se: C, 63.01; H, 6.61; N, 6.12; Se, 17.26. Found: C,62.88; H, 6.83; N, 6.02; Se, 16.91. ##STR51##

EXAMPLE XXXVI3,6-Dibenzylhexahydro-8a-methoxy-5H-4a,8-(methanothiomethano)-2H-pyrido[3,4-e]-1,3-oxazinedihydroperchlorate (77)

A 125-mL, Erlenmeyer flask was charged with a solution of ketal3,6-dibenzylhexahydro-8a-methoxy-5H-4a,8-(methanothiomethano)-2H-pyrido[3,4-e]-1,3-oxazine(1.00 g, 2.44 mmol) in benzene (20 mL). To this solution was addeddropwise over 15 min a solution of HClO₄ (60%, 1.00 g, 5.97 mmol) in2-propanol (5 mL) with vigorous stirring (magnetic). This precipitatedthe salt as a white powdery solid. To prevent caking of the precipitateit was found necessary to add additional 2-propanol (10 mL). The mixturewas stirred an additional 1 hour at room temperature. The salt wasfiltered, recrystallized (ethanol, 25 mL), and dried (Abderhalden, P₂O₅, 77° C., vacuum pump, 12 hours) to afford3,6-dibenzylhexahydro-8a-methoxy-5H-4a,8-(methanothiomethano)-2H-pyrido[3,4-e]-1,3-oxazinedihydroperchlorate (0.60 g, 40%) as white crystals: mp 160°-162° C.(dec); IR (KBr) cm⁻¹ 2760-2845 (N⁺ --H), 1080 (CL--O); ¹ H NMR (DMSO-d₆)δ2.17 [d, J=11.7 Hz, 1H, H(4)az], 2.35 [d, J=11.7 Hz, 1H, H(4)eq], 2.43[d, J=13.0 Hz, 1H, H(11)ax], 2.64 [br s, 1H, H(8)], 2.76 [d, J=13.6 Hz,1H, H(9)ax], 3.00 [d, J=13.0 Hz, H(11)eq], 3.18 [s, 3H, CH₃ O], 3.22 [m,2H, H(9)eq and ArCH₂ ], 3.32 [d, J=13.6 Hz, 1H, H(5)ax], 3.46 [d, J=12.0Hz, H(7)ax], 3.57 [d, J=13.6 Hz, 1H, H(5 )eq], 3.79 [d, J=12.0 Hz,H(7)eq], 4.00 [d, J=7.3 Hz, 1H, H(2)ax], 4.19 [d, J=12.0 Hz, 1H ArCH₂ ],4.24 [d, J=7.3 Hz, 1H, H(2)eq], 4.40 [dd, J=12.6, 5.9 Hz, ArCH₂ ], 4.54[dd, J=12.6, 3.9 Hz, 1H, ArCH₂ ], 7.25-7.39 [m, 5H, ArH], 9.53 [br s,1H, N⁺ --H]; ¹³ C NMR (DMSO-d₆) ppm 28.26 [t, C(9)], 31.34 [d, C(8)],31.80 [t, C(11)], 37.39 [s, C(4a)], 46.36 [q, CH₃ O], 52.33 [T, C(4)],54.25 [t, C(7)], 55.40 [t, C(5)], 56.21 [t, ArCH₂ ], 60.20 [t, ArCH₂ ],78.00 [t, C(2)], 93.75 [s, C(8a)], 127.14, 128.27, 129.09, 129.65,130.60, 136.98 [ArC]. Analysis calculated for C₂₄ H₃₀ N₂ N₂ O₂ S.2 HClO₄: C, 47.14; H, 5.27; Cl, 11.59; N, 4.58; S, 5.24. Found: C, 47.22; H,5.14; Cl, 11.38; N, 4.44; S, 5.47. ##STR52##

In order to illustrate the useful biological activity of the compoundsaccording to the present invention, selected derivatives were testedusing dog models for antiarrhythmic activity. The clinically used druglidocaine was employed as a basis for comparison. In the dog model aninfarction was created in a small area of the heart and thereafter anelectrical pacing was administered to generate a sustained ventriculartachycardia (VT). This irregular bearing pattern of the heart results ina reduction of the heart's pumping capacity in a manner now accepted asresembling symptoms observed in humans during heart attack (see:Scherlag, B. J. et al. Am. J. Cardiol. 1983, 51, 207; Bailey, B. B. etal, J. Med. Chem., 1984, 27, 759; and U.S. Pat. No. 4,581,361 forfurther details, said references incorporated herein for such purposes).The effects of the selected compounds in terms of ability to reduce therate of the ventricular tachycardia or to eliminate the same (i.e., tonot allow VT to be sustained) is then evaluated and compared to the druglidocaine. The following Table contains the data observed as result ofthe testing.

                  TABLE                                                           ______________________________________                                        Antiaarhythmic Data for Representative Compounds of the 3,7-                  Diheterabicyclo[3.3.1]nonanes and Derivatives                                                           3 mg/kg.sup.c                                                                           6 mg/kg.sup.d                             Com-  Pacing          Rate of    Rate of     Rate of                          pound Rate*   MBP.sup.a                                                                             SVT.sup.b                                                                           MBP  SVT    MBP  SVT                              ______________________________________                                              450(C).sup.e                                                                          170.sup.g                                                                             450                                                                   (50).sup.h                                                            450(L).sup.f               375                                          (45)  450                   100.sup.i                                                                          330                                                330(C)  160.sup.g                                                                             330                                                                   (70).sup.h                                                      (47)  330                        240         270                                                                           (NS)                                   330(C)  160.sup.g                                                                             330                                                                   (70).sup.h                                                      (50)  330                   85   300    70   310                                    330(C)  70.sup.h                                                                              270                                                           390(L)                     270(NS)                                            360(L)                                 240                              (66)  360                   95   330(NS)                                      (66)  390                               95   240                                    360(C)  90.sup.h                                                                              390                                                           330(L)                     300                                                300(L)                                 270                              (66)  390                   99   (NS)                                               390(C)  90.sup.h                                                                              390                                                           390(L)                     300                                                390(L)                     300         270                              (65)  390                   92   210                                          (65)  390                               85   (NS)                                   390(C)  102.sup.h                                                                             390                                                           390(L)                     330                                                390(L)                                 210                              (28)  390                   99   330                                                390(C)  70.sup.h                                                                              390                                                           360(L)                     360                                                360(L)                                 330                              (71)  390                   85   340                                                360(C)  80.sup.8                                                                              330                                                           390(L)                     360                                                330(L)                                 210                              (72)  360                   90   330                                          (72)  390                               86   330                                    330(C)  70.sup.h                                                                              330                                                     (59**)                                                                              330                   70   300                                          (59**)                                                                              330                               75   280                                    390(C)  95.sup.h                                                                              (NS)                                                          390(L)                     No VT                                              360(L)                                 270                              (77)  390                   98   330                                          (77)  390                               101  330                              ______________________________________                                         .sup.a Mean Blood Pressure during normal sinus rhythm beforea VT is           induced.                                                                      .sup.b Sustained Ventricular tachycardia                                      .sup.c 3 mg of compound per kg of dog model                                   .sup.d 6 mg of compound per kg of dog model                                   .sup.e(C) Control before compound is added to dog model                       .sup.f(L) Lidocaine                                                           .sup.g MBP before compound is added to dog model                              .sup.h MBP during sustained VT                                                .sup.i MBP during sustained VT                                                .sup.j(NS) Nonsustained VT                                                    *Electrically stimupacing rate required to induce an SVT                      **endoexo isomer                                                         

From the Table, it is concluded that the compound (45) was extremelyeffective in reducing the ventricular tachycardia (as compared tolidocaine) at a concentration of only 3 mg/kg. The same was true incompounds (28), (50), (59**), (71), and (72). In (47), (65), and (66),the VT generated in the dog model was virtually eliminated by thecompound and a normal sinus rhythm was observed. Thus, the generated VTwas not sustained in the presence of the compound. In contrast, the VTwas sometimes reduced by the presence of lidocaine, but was rarelyeliminated. Thus, the heterocycles claimed in the application appear tohave electrocardiology properties equal or superior to lidocaine, aclinically used drug for the treatment of victims of heart attacks. Thisin combination with the possibility that the hetera atoms afford the useof a radioactive isotope for imagining (e.g., the use of ⁷⁵ Se) purposescreates the possibility of in vivo analysis simultaneously withtherapeutic treatment.

In principle, it is felt that the compositions of the present inventioncan be employed by themselves, in combination with each other, or incombination with other drugs to achieve either individually or incombination the desired antiarrhythmic properties. It is envisioned thatthe composition can be utilized and administered in a variety of methodsincluding by way of example, but not limited thereto, intravenously,orally, by suppository, by inhalation, and the like. Furthermore, it isgenerally felt that the compositions as claimed either specificallypossess antiarrhythmic activity or generally are broadly biologicallyactive or the respective compositions are intermediaries toantiarrhythmic and biologically active species that are released orcreated in situ as the result of the administration of the drug.

Having thus described and exemplified the preferred embodiments with acertain degree of particularity, it is to be understood that theinvention is not to be limited to the embodiments set forth herein forpurposes of exemplification, but is to be limited only by the scope ofthe attached claims, including a full range of equivalents to which eachelement thereof is entitled.

We claim:
 1. A polyheterotricyclo compound having the formulae:##STR53## where Ar is ##STR54## Z is S, Se, O, CHR' or NR'; X⁻ is ClO₄⁻, Cl⁻, Br⁻, or I⁻ ;R is CH₃, C₂ H₅, C₃ H₇ or C₄ -C₉ alkyl; and R' is H,CH₃, C₂ H₅, or C(CH₃)₃.
 2. A polyheterotricyclo compound of claim 1wherein Ar is ##STR55##
 3. A polyheterotricyclo compound of claim 2where Z is Se.
 4. A polyheterotricyclo compound of claim 2 where Z is S.5. A polyheterotricyclo compound of claim 3 where R is CH₃.
 6. Apolyheterotricyclo compound of claim 4 where R is CH₃.
 7. Apolyheterotricyclo compound of claim 5 where X⁻ is ClO₄ ⁻.
 8. Apolyheterotricyclo compound of claim 6 where X⁻ is ClO₄ ⁻.